Oxadiazepinone derivatives and methods of treating hepatitis b infections

ABSTRACT

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof, pharmaceutical compositions thereof, and methods of inhibiting, suppressing, or preventing HBV infection in the subject.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 16/313,984, filed Dec. 28, 2018, which application is a U.S.C. § 371 filing of International Application No PCT/US2017/040130, filed Jun. 29, 2017 which application claims benefit of U.S. provisional patent application No. 62/356,487, filed Jun. 29, 2016; and U.S. provisional patent application No. 62/511,565, filed May 26, 2017; the entire contents of each of which are incorporated herein by reference.

BACKGROUND

Chronic hepatitis B virus (HBV) infection is a significant global health problem, affecting over 5% of the world population (over 350 million people worldwide and 1.25 million individuals in the U.S.).

Despite the availability of a prophylactic HBV vaccine, the burden of chronic HBV infection continues to be a significant unmet worldwide medical problem, due to suboptimal treatment options and sustained rates of new infections in most parts of the developing world. Current treatments do not provide a cure and are limited to only two classes of agents (interferon alpha and nucleoside analogues/inhibitors of the viral polymerase); drug resistance, low efficacy, and tolerability issues limit their impact. The low cure rates of HBV are attributed at least in part to the fact that complete suppression of virus production is difficult to achieve with a single antiviral agent. However, persistent suppression of HBV DNA slows liver disease progression and helps to prevent hepatocellular carcinoma. Current therapy goals for HBV-infected patients are directed to reducing serum HBV DNA to low or undetectable levels, and to ultimately reducing or preventing the development of cirrhosis and hepatocellular carcinoma.

The HBV capsid protein plays essential functions during the viral life cycle. HBV capsid/core proteins form metastable viral particles or protein shells that protect the viral genome during intercellular passage, and also play a central role in viral replication processes, including genome encapsidation, genome replication, and virion morphogenesis and egress. Capsid structures also respond to environmental cues to allow un-coating after viral entry. Consistently, the appropriate timing of capsid assembly and dis-assembly, the appropriate capsid stability and the function of core protein have been found to be critical for viral infectivity.

There is a need in the art for therapeutic agents that can increase the suppression of virus production and that can treat, ameliorate, or prevent HBV infection. Administration of such therapeutic agents to an HBV infected patient, either as monotherapy or in combination with other HBV treatments or ancillary treatments, will lead to significantly reduced virus burden, improved prognosis, diminished progression of the disease and enhanced seroconversion rates.

SUMMARY

Provided herein are compounds useful for the treatment of HBV infection in a subject in need thereof. Thus, in an aspect, provided herein is a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein

A is N or C(H);

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, or C₁-C₆-alkyl-OH;

R² is, at each occurrence, independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl, (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl, —C(O)C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl-CN, —C(O)C₃-C₇-cycloalkyl, —C(O)O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-haloalkyl, —C(O)O—C₃-C₇-cycloalkyl, —C(O)N(R¹⁰)₂, —S(O)₂C₁-C₆-alkyl, —S(O)₂C₁-C₆-haloalkyl and —S(O)₂C₃-C₇-cycloalkyl;

or wherein two R⁷ groups together with the N to which they are attached form a C₂-C₆ heterocycle, wherein the C₂-C₆ heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R¹⁰ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H and C₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4.

In another aspect, provided herein is a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, or C₁-C₆-alkyl-OH;

R² is, at each occurrence, independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl, (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H and C₁-C₆-alkyl;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4.

In an embodiment, the compound of Formula Ia has the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a compound of Formula III:

or a pharmaceutically acceptable salt thereof, wherein

is a single or double bond;

X is N—R^(c);

R¹ is H, C₁-C₆-alkyl, C₁-C₆-alkenyl, or C₁-C₆-alkyl-OH;

R² is, at each occurrence, independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH and halo;

R³ is, at each occurrence, independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl, (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁵ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl, —C(O)C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl-CN, —C(O)C₃-C₇-cycloalkyl, —C(O)O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-haloalkyl, —C(O)O—C₃-C₇-cycloalkyl, —C(O)N(R¹⁰)₂, —S(O)₂C₁-C₆-alkyl, —S(O)₂C₁-C₆-haloalkyl and —S(O)₂C₃-C₇-cycloalkyl;

or wherein two R⁷ groups together with the N to which they are attached form a C₂-C₆ heterocycle, wherein the C₂-C₆ heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R¹⁰ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H and C₁-C₆-alkyl;

R^(c) is absent, H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-haloalkyl, or C₁-C₆-alkyl-OH;

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4; and

p is 0, 1, 2, 3, or 4.

In another aspect, provided herein is a pharmaceutical composition comprising at least one compound of Formula Ia, Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

In another aspect, provided herein is a pharmaceutical composition comprising at least one disclosed compound, together with a pharmaceutically acceptable carrier. In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula Ia, Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula Ia, Formula I, Formula II, or Formula III, or a pharmaceutically acceptable salt thereof.

In an embodiment, any of the methods provided herein can further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, interferon, viral entry inhibitor, viral maturation inhibitor, capsid assembly modulator, reverse transcriptase inhibitor, a cyclophilin/TNF inhibitor, a TLR-agonist, an HBV vaccine, and any combination thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray crystal structure of the iodo-benzoic acid analogue of Intermediate 18, also referred to as compound 215.

DETAILED DESCRIPTION

Provided herein are compounds, e.g., the compounds of Formula Ia, Formula I, Formula II, or Formula III, or pharmaceutically acceptable salts thereof, that are useful in the treatment and prevention of HBV infection in subject.

Without being bound to any particular mechanism of action, these compounds are believed to modulate or disrupt HBV assembly and other HBV core protein functions necessary for HBV replication or the generation of infectious particles. In addition, or alternatively, the compounds may disrupt HBV capsid assembly to induce production of defective viral particles with greatly reduced infectivity or replication capacity. In other words, the compounds provided herein may act as capsid assembly modulators by modulating (e.g., accelerating, delaying, inhibiting, disrupting or reducing) normal viral capsid assembly or disassembly, binding capsids, and/or altering metabolism of cellular polyproteins and precursors. The modulation may occur when the capsid protein is mature, or during viral infectivity. The disclosed compounds can be used in methods of modulating the activity or properties of HBV cccDNA, or the generation or release of HBV RNA particles from within an infected cell.

In one embodiment, the compounds described herein are suitable for monotherapy and are effective against natural or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds described herein are suitable for use in combination therapy.

Definitions

Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are those well-known and commonly employed in the art.

As used herein, the articles “a” and “an” refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting.

As used herein, the term “about” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. As used herein when referring to a measurable value such as an amount, a temporal duration, and the like, the term “about” is meant to encompass variations of ±20% or ±10%, including ±5%, ±1%, and ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.

As used herein, the term “capsid assembly modulator” refers to a compound that disrupts or accelerates or inhibits or hinders or delays or reduces or modifies normal capsid assembly (e.g., during maturation) or normal capsid disassembly (e.g., during infectivity) or perturbs capsid stability, thereby inducing aberrant capsid morphology and function. In one embodiment, a capsid assembly modulator accelerates capsid assembly or disassembly, thereby inducing aberrant capsid morphology. In another embodiment, a capsid assembly modulator interacts (e.g. binds at an active site, binds at an allosteric site, modifies or hinders folding and the like) with the major capsid assembly protein (CA), thereby disrupting capsid assembly or disassembly. In yet another embodiment, a capsid assembly modulator causes a perturbation in structure or function of CA (e.g., ability of CA to assemble, disassemble, bind to a substrate, fold into a suitable conformation, or the like), which attenuates viral infectivity or is lethal to the virus.

As used herein, the term “treatment” or “treating” is defined as the application or administration of a therapeutic agent, i.e., a disclosed compound (alone or in combination with another pharmaceutical agent), to a patient, or application or administration of a therapeutic agent to an isolated tissue or cell line from a patient (e.g., for diagnosis or ex vivo applications), who has an HBV infection, a symptom of HBV infection or the potential to develop an HBV infection, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the HBV infection, the symptoms of HBV infection, or the potential to develop an HBV infection. Such treatments may be specifically tailored or modified, based on knowledge obtained from the field of pharmacogenomics.

As used herein, the term “prevent” or “prevention” means no disorder or disease development if none had occurred, or no further disorder or disease development if there had already been development of the disorder or disease. Also considered is the ability of one to prevent some or all of the symptoms associated with the disorder or disease.

As used herein, the term “patient,” “individual” or “subject” refers to a human or a non-human mammal. Non-human mammals include, for example, livestock and pets, such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably, the patient, subject, or individual is human.

As used herein, the terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, the term “pharmaceutically acceptable salt” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present invention include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

As used herein, the term “composition” or “pharmaceutical composition” refers to a mixture of at least one compound useful within the invention with a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques of administering a compound exist in the art including, but not limited to, intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

As used herein, the term “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition or carrier, such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound useful within the invention within or to the patient such that it may perform its intended function. Typically, such constructs are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound useful within the invention, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound useful within the invention, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound useful within the invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of the invention are known in the art and described, for example in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, Pa.), which is incorporated herein by reference. As used herein, the term “alkyl,” by itself or as part of another substituent means, unless otherwise stated, a straight or branched chain hydrocarbon having the number of carbon atoms designated (i.e., C₀-C₆-alkyl means null or an alkyl having one to six carbon atoms) and includes straight and branched chains. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, and hexyl. Other examples of C₁-C₆-alkyl include ethyl, methyl, isopropyl, isobutyl, n-pentyl, and n-hexyl.

As used herein, the term “alkenyl,” denotes a monovalent group derived from a hydrocarbon moiety containing at least two carbon atoms and at least one carbon-carbon double bond. The double bond may or may not be the point of attachment to another group. Alkenyl groups (e.g., C₂-C₈-alkenyl) include, but are not limited to, for example, ethenyl, propenyl, prop-1-en-2-yl, butenyl, l-methyl-2-buten-1-yl, heptenyl, octenyl and the like.

As used herein, the term “halo” or “halogen” alone or as part of another substituent means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine, more preferably, fluorine or chlorine.

As used herein, the term “haloalkyl” refers to alkyl radicals wherein any one or more of the alkyl carbon atoms is substituted with halo as defined above. Haloalkyl embraces monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. The term “haloalkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, and pentafluoroethyl.

As used herein, the term “cycloalkyl” refers to a mono cyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In one embodiment, the cycloalkyl group is saturated or partially unsaturated. In another embodiment, the cycloalkyl group is fused with an aromatic ring. Cycloalkyl groups include groups having 3 to 10 ring atoms (C₃-C₁₀-cycloalkyl), groups having 3 to 8 ring atoms (C₃-C₈-cycloalkyl), groups having 3 to 7 ring atoms (C₃-C₇-cycloalkyl), and groups having 3 to 6 ring atoms (C₃-C₆-cycloalkyl). Monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Dicyclic cycloalkyls include, but are not limited to, tetrahydronaphthyl, indanyl, and tetrahydropentalene. Polycyclic cycloalkyls include adamantine and norbornane. The term cycloalkyl includes unsaturated nonaromatic cyclic groups, which contain at least one carbon carbon double bond or one carbon carbon triple bond.

As used herein, the term “heterocycloalkyl” or “heterocyclyl” refers to a heteroalicyclic group containing one to four ring heteroatoms each selected from O, S, and N. In one embodiment, each heterocyclyl group has from 3 to 10 atoms in its ring system, with the proviso that the ring of said group does not contain two adjacent O or S atoms. Heterocyclyl substituents may be alternatively defined by the number of carbon atoms, e.g., C₂-C₈-heterocyclyl indicates the number of carbon atoms contained in the heterocyclic group without including the number of heteroatoms. For example, a C₂-C₈-heterocyclyl will include an additional one to four heteroatoms. Preferably, the heterocyclyl group has less than three heteroatoms. More preferably, the heterocyclyl group has one to two heteroatoms. In another embodiment, the heterocycloalkyl group is fused with an aromatic ring. In one embodiment, the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. The heterocyclic system may be attached, unless otherwise stated, at any heteroatom or carbon atom that affords a stable structure.

An example of a 3-membered heterocyclyl group includes, and is not limited to, aziridine. Examples of 4-membered heterocycloalkyl groups include, and are not limited to, azetidine and a beta lactam. Examples of 5-membered heterocyclyl groups include, and are not limited to, pyrrolidine, oxazolidine and thiazolidinedione. Examples of 6-membered heterocycloalkyl groups include, and are not limited to, piperidine, morpholine, and piperazine.

Other non-limiting examples of heterocyclyl groups include monocyclic groups such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, pyrroline, pyrazolidine, imidazoline, dioxolane, sulfolane, 2,3-dihydrofuran, 2,5-dihydrofuran, tetrahydrofuran, thiophane, piperidine, 1,2,3,6-tetrahydropyridine, 1,4-dihydropyridine, piperazine, morpholine, thiomorpholine, pyran, 2,3-dihydropyran, tetrahydropyran, 1,4-dioxane, 1,3-dioxane, homopiperazine, homopiperidine, 1,3-dioxepane, 4,7-dihydro-1,3-dioxepin, and hexamethyleneoxide.

As used herein, the term “aromatic” refers to a carbocycle or heterocycle with one or more polyunsaturated rings and having aromatic character, i.e., having (4n+2) delocalized π (pi) electrons, where n is an integer.

As used herein, the term “aryl,” employed alone or in combination with other terms, means, unless otherwise stated, a carbocyclic aromatic system containing one or more rings (typically one, two, or three rings), wherein such rings may be attached together in a pendent manner, such as a biphenyl, or may be fused, such as naphthalene. Examples of aryl groups include phenyl, anthracyl, and naphthyl. Preferred examples are phenyl (e.g., C₆-aryl) and biphenyl (e.g., C₁₂-aryl). In some embodiments, aryl groups have from six to sixteen carbon atoms. In some embodiments, aryl groups have from six to twelve carbon atoms (e.g., C₆-C₁₂-aryl). In some embodiments, aryl groups have six carbon atoms (e.g., C₆-aryl). As used herein, the term “heteroaryl” or “heteroaromatic” refers to a heterocycle having aromatic character. Heteroaryl substituents may be defined by the number of carbon atoms, e.g., C₁-C₉-heteroaryl indicates the number of carbon atoms contained in the heteroaryl group without including the number of heteroatoms. For example, a C₁-C₉-heteroaryl will include an additional one to four heteroatoms. Preferably, the heteroaryl group has less than three heteroatoms. More preferably, the heteroaryl group has one to two heteroatoms. A polycyclic heteroaryl may include one or more rings that are partially saturated. Non-limiting examples of heteroaryls include pyridyl, pyrazinyl, pyrimidinyl (including, e.g., 2- and 4-pyrimidinyl), pyridazinyl, thienyl, furyl, pyrrolyl (including, e.g., 2-pyrrolyl), imidazolyl, thiazolyl, oxazolyl, pyrazolyl (including, e.g., 3- and 5-pyrazolyl), isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

Non-limiting examples of polycyclic heterocycles and heteroaryls include indolyl (including, e.g., 3-, 4-, 5-, 6- and 7-indolyl), indolinyl, quinolyl, tetrahydroquinolyl, isoquinolyl (including, e.g., 1- and 5-isoquinolyl), 1,2,3,4-tetrahydroisoquinolyl, cinnolinyl, quinoxalinyl (including, e.g., 2- and 5-quinoxalinyl), quinazolinyl, phthalazinyl, 1,8-naphthyridinyl, 1,4-benzodioxanyl, coumarin, dihydrocoumarin, 1,5-naphthyridinyl, benzofuryl (including, e.g., 3-, 4-, 5-, 6- and 7-benzofuryl), 2,3-dihydrobenzofuryl, 1,2-benzisoxazolyl, benzothienyl (including, e.g., 3-, 4-, 5-, 6-, and 7-benzothienyl), benzoxazolyl, benzothiazolyl (including, e.g., 2-benzothiazolyl and 5-benzothiazolyl), purinyl, benzimidazolyl (including, e.g., 2-benzimidazolyl), benzotriazolyl, thioxanthinyl, carbazolyl, carbolinyl, acridinyl, pyrrolizidinyl, and quinolizidinyl.

As used herein, the term “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to another group.

As used herein, the terminology “selected from . . . ” (e.g., “R⁴ is selected from A, B and C”) is understood to be equivalent to the terminology “selected from the group consisting of . . . ” (e.g., “R⁴ is selected from the group consisting of A, B and C”).

Compounds

Provided herein are compounds having the structure of Formula Ia:

or a pharmaceutically acceptable salt thereof.

A may be N or C(H). In embodiments, A is N. In embodiments, A is C(H).

R¹ may be H, C₁-C₆-alkyl, C₁-C₆-alkenyl, or C₁-C₆-alkyl-OH. In embodiments, R¹ is H. In embodiments, R¹ is C₁-C₆-alkyl. In embodiments, R¹ is C₁-C₆-alkenyl. In embodiments, R¹ is C₁-C₆-alkyl-OH.

In embodiments, there may be 0, 1, 2, 3, or 4 R² substituents: m is 0, 1, 2, 3, or 4. Each R² may be independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, or C₀-C₆-alkyl-C(O)N(R⁷)₂. In certain embodiments, m is 0 and there is no R² substitution. In certain embodiments, m is 1 and there is one R² substitution. In certain embodiments, m is 2 and there are two R² substitutions. In certain embodiments, m is 3 and there are three R² substitutions. In certain embodiments, m is 4 and there are four R² substitutions. In embodiments, there may be 0, 1, 2, 3, or 4 R³ substituents: n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R³ substitution. In certain embodiments, nisi and there is one R³ substitution. In certain embodiments, n is 2 and there are two R³ substitutions. In certain embodiments, n is 3 and there are three R³ substitutions. In certain embodiments, n is 4 and there are four R³ substitutions.

In certain embodiments, R² may be C₁-C₆-alkyl optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, R² may be C₀-C₆-alkyl-OR⁶, wherein R⁶ is C₁-C₆-haloalkyl. In certain embodiments, R² may be (CH₂)₁₋₂—O—C₁-C₃-alkyl, wherein C₁-C₃-alkyl is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, m is 1 or 2.

Each R³ may be independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, at least one R³ is —OH. In certain embodiments, at least one R³ is halo. In certain embodiments, at least one R³ is C₁-C₆-alkyl. In certain embodiments, at least one R³ is C₁-C₆-haloalkyl. In certain embodiments, at least one R³ is —O—C₁-C₆-alkyl. In certain embodiments, at least one R³ is C₁-C₆-alkyl-OH.

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl, (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In a particular embodiment, R⁴ is phenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In another particular embodiment, R⁴ is pyridyl, wherein the pyridyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl.

R⁵ may be selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In a particular embodiment, R⁵ is H.

R⁶ may be selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl. In a particular embodiment, R⁶ is selected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

R⁷ may be independently selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl, —C(O)C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl-CN, —C(O)C₃-C₇-cycloalkyl, —C(O)O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-haloalkyl, —C(O)O—C₃-C₇-cycloalkyl, —C(O)N(R¹⁰)₂, —S(O)₂C₁-C₆-alkyl, —S(O)C₁-C₆-haloalkyl and —S(O)₂C₃-C₇-cycloalkyl;

or wherein two R⁷ groups together with the N to which they are attached form a C₂-C₆ heterocycle, wherein the C₂-C₆ heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents. In an embodiment, R⁷ is, at each occurrence, independently selected from H and C₁-C₆-alkyl. In a further embodiment, R⁷ is, at each occurrence, independently selected from H, C₁-C₆-haloalkyl, C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl, —C(O)C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl-CN, —C(O)C₃-C₇-cycloalkyl, —C(O)O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-haloalkyl, —C(O)O—C₃-C₇-cycloalkyl, —C(O)N(R¹⁰)₂, —S(O)₂C₁-C₆-alkyl, —S(O)₂C₁-C₆-haloalkyl or —S(O)₂C₃-C₇-cycloalkyl. In an embodiment, R⁷ is, at each occurrence, independently selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl, —C(O)C₁-C₆-haloalkyl, —C(O)C₁-C₆-alkyl-OR¹⁰, —C(O)C₁-C₆-alkyl-CN, —C(O)C₃-C₇-cycloalkyl, —C(O)O—C₁-C₆-alkyl, —C(O)O—C₁-C₆-haloalkyl, —C(O)O—C₃-C₇-cycloalkyl, —C(O)N(R¹⁰)₂, —S(O)₂C₁-C₆-alkyl, —S(O)₂C₁-C₆-haloalkyl or —S(O)₂C₃-C₇-cycloalkyl.

R⁸ may be selected from H and C₁-C₆-alkyl.

R⁹ may be selected from H and C₁-C₆-alkyl.

R¹⁰ may be selected from H and C₁-C₆-alkyl.

R^(a) may be independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH.

R^(b) may be independently selected from H and C₁-C₆-alkyl.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

In another aspect, provided herein are compounds having the structure of Formula I:

or a pharmaceutically acceptable salt thereof.

R¹ may be H, C₁-C₆-alkyl, C₁-C₆-alkenyl, or C₁-C₆-alkyl-OH. In embodiments, R¹ is H. In embodiments, R¹ is C₁-C₆-alkyl. In embodiments, R¹ is C₁-C₆-alkenyl. In embodiments, R¹ is C₁-C₆-alkyl-OH.

In embodiments, there may be 0, 1, 2, 3, or 4 R² substituents: m is 0, 1, 2, 3, or 4. Each R² may be independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, or C₀-C₆-alkyl-C(O)N(R⁷)₂. In certain embodiments, m is 0 and there is no R² substitution. In certain embodiments, m is 1 and there is one R² substitution. In certain embodiments, m is 2 and there are two R² substitutions. In certain embodiments, m is 3 and there are three R² substitutions. In certain embodiments, m is 4 and there are four R² substitutions. In embodiments, there may be 0, 1, 2, 3, or 4 R³ substituents: n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R³ substitution. In certain embodiments, nisi and there is one R³ substitution. In certain embodiments, n is 2 and there are two R³ substitutions. In certain embodiments, n is 3 and there are three R³ substitutions. In certain embodiments, n is 4 and there are four R³ substitutions.

In certain embodiments, R² may be C₁-C₆-alkyl optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, R² may be C₀-C₆-alkyl-OR⁶, wherein R⁶ is C₁-C₆-haloalkyl. In certain embodiments, R² may be (CH₂)₁₋₂—O—C₁-C₃-alkyl, wherein C₁-C₃-alkyl is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, m is 1 or 2.

Each R³ may be independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, at least one R³ is —OH. In certain embodiments, at least one R³ is halo. In certain embodiments, at least one R³ is C₁-C₆-alkyl. In certain embodiments, at least one R³ is C₁-C₆-haloalkyl. In certain embodiments, at least one R³ is —O—C₁-C₆-alkyl. In certain embodiments, at least one R³ is C₁-C₆-alkyl-OH. R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl, (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In a particular embodiment, R⁴ is phenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In another particular embodiment, R⁴ is pyridyl, wherein the pyridyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl.

R⁵ may be selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In a particular embodiment, R⁵ is H.

R⁶ may be selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl. In a particular embodiment, R⁶ is selected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

R⁷ may be independently selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In a particular embodiment, R⁷ is, at each occurrence, independently selected from H, and C₁-C₆-alkyl.

R⁸ may be selected from H and C₁-C₆-alkyl.

R⁹ may be selected from H and C₁-C₆-alkyl.

R^(a) may be independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH.

R^(b) may be independently selected from H and C₁-C₆-alkyl.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

In another aspect, provided herein are compounds having the structure of Formula III:

or a pharmaceutically acceptable salt thereof.

may be a single bond or a double bond. In embodiments,

is a single bond.

In embodiments,

is a double bond.

X is N—R^(c).

R¹ may be H, C₁-C₆-alkyl, C₁-C₆-alkenyl, or C₁-C₆-alkyl-OH. In embodiments, R¹ is H. In embodiments, R¹ is C₁-C₆-alkyl. In embodiments, R¹ is C₁-C₆-alkenyl. In embodiments, R¹ is C₁-C₆-alkyl-OH.

In embodiments, there may be 0, 1, 2, 3, or 4 R² substituents: m is 0, 1, 2, 3, or 4. Each R² may be independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-alkylene, C₀-C₆-alkyl-C₃-C₆-cycloalkyl, C₀-C₆-alkyl-C₂-C₆-heterocycloalkyl, C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, or C₀-C₆-alkyl-C(O)N(R⁷)₂. In certain embodiments, m is 0 and there is no R² substitution. In certain embodiments, m is 1 and there is one R² substitution. In certain embodiments, m is 2 and there are two R² substitutions. In certain embodiments, m is 3 and there are three R² substitutions. In certain embodiments, m is 4 and there are four R² substitutions. In embodiments, there may be 0, 1, 2, 3, or 4 R³ substituents: n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0 and there is no R³ substitution. In certain embodiments, nisi and there is one R³ substitution. In certain embodiments, n is 2 and there are two R³ substitutions. In certain embodiments, n is 3 and there are three R³ substitutions. In certain embodiments, n is 4 and there are four R³ substitutions.

Each R³ may be independently selected from —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, at least one R³ is —OH. In certain embodiments, at least one R³ is halo. In certain embodiments, at least one R³ is C₁-C₆-alkyl. In certain embodiments, at least one R³ is C₁-C₆-haloalkyl. In certain embodiments, at least one R³ is —O—C₁-C₆-alkyl. In certain embodiments, at least one R³ is C₁-C₆-alkyl-OH.

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl, (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, and (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl, wherein heteroaryl, aryl, cycloalkyl, and heterocycloalkyl are optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is (CR^(a)R^(b))_(p)—C₂-C₆-heterocycloalkyl optionally substituted with 1, 2, 3, or 4 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In certain embodiments, R⁴ is phenyl or pyridyl, wherein said phenyl or pyridyl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In a particular embodiment, R⁴ is phenyl, wherein the phenyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl. In another particular embodiment, R⁴ is pyridyl, wherein the pyridyl is substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, C₁-C₆-alkyl and C₁-C₆-haloalkyl.

R⁵ may be selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In a particular embodiment, R⁵ is H.

R⁶ may be selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl. In a particular embodiment, R⁶ is selected from H, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

R⁷ may be independently selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH. In a particular embodiment, R⁷ is, at each occurrence, independently selected from H, and C₁-C₆-alkyl.

R⁸ may be selected from H and C₁-C₆-alkyl.

R⁹ may be selected from H and C₁-C₆-alkyl.

R^(a) may be independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH.

R^(b) may be independently selected from H and C₁-C₆-alkyl.

R^(c) may be selected from absent, H, C₁-C₆-alkyl, C₁-C₆-alkenyl, C₁-C₆-haloalkyl, or C₁-C₆-alkyl-OH.

m may be 0, 1, 2, 3, or 4.

n may be 0, 1, 2, 3, or 4.

p may be 0, 1, 2, 3, or 4.

In an embodiment of the compound of Formula III, n is 0, 1, or 2; and each R³ is independently C₁-C₆-alkyl.

In another embodiment of the compound of Formula III, R⁴ is phenyl, pyridinyl, or cyclohexyl, wherein R⁴ is optionally substituted with 1, 2, or 3 groups, each independently selected from —F, —Br, —Cl, —I, —CN, —CH₃, —CH₂CH₃, —CF₃, —CHF₂, and —SF₅.

In yet another embodiment of the compound of Formula III, R¹ is CH₃;

R² is selected from the group consisting of: H, C₁₋₄haloalkyl, OH, C₁₋₄alkyl, CH₂OH,

CH(OH)CH₃, CH(OH)CH₂CH₃, CH(OH)cyclopropyl, and CH₂OCH₂CHF₂;

R³ is H or CH₃;

R⁴ is

R⁵ is H;

R^(c) is absent, H, C₁₋₄alkyl, CH₂CH═CH₂, CH₃CHF₂, CH₂CH₂OH, CH₂CH₂CH₂OH, or CH₂CH(OH)CH₃;

m is 0, 1, or 2; and

n is 0 or 1.

In an embodiment of the compound of Formula Ia, R¹ is C₁-C₆-alkyl, or C₁-C₆-alkenyl.

In another embodiment of the compound of Formula Ia, R¹ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH═CH₂, or —CD₃.

In an embodiment of the compound of Formula Ia, m is 1 or 2; and

each R² is independently selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₀-C₆-alkyl-OR⁶; C₁-C₆-alkyl-(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂.

In an embodiment of the compound of Formula I, R¹ is C₁-C₆-alkyl, or C₁-C₆-alkenyl.

In another embodiment of the compound of Formula I, R¹ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH═CH₂, or —CD₃.

In an embodiment of the compound of Formula I, m is 1 or 2; and

each R² is independently selected from C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₀-C₆-alkyl-OR⁶; C₁-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂.

In an embodiment, the compound of Formula Ia has the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

In an embodiment of the compound of Formula Ia or Formula II, R² is C₀-C₆-alkyl-OR⁶, C₀-C₆-alkyl-C(O)N(R⁷)₂ and C₁-C₆-alkyl-N(R⁷)₂.

In an embodiment of the compound of Formula Ia or Formula II, R² is selected from the group consisting of —CH₂OH, —CH₂OCF₃, —C(O)-3,3-difluoroazetidine, —C(O)-3,3-difluoropyrrolidine, —C(O)N(CH₃)(CH₂CHF₂), —C(O)N(CH₃)(CH₂CF₃), —C(O)N(H)(CH₂CHF₂), —C(O)N(H)(CH₃), —C(O)N(H)(CH₂CF₃), —CH₂N(H)(C(O)CH₃), —CH₂N(H)(C(O)CF₃), —CH₂N(H)(C(O)OCH₃), —CH₂N(H)(S(O)₂CH₃), —CH₂N(H)(S(O)₂CF₃), —CH₂-pyrrolidin-2-one, —CH₂N(H)(C(O)CH₂CH₃), —CH₂N(H)(C(O)-cyclopropyl), —CH₂N(H)(C(O)CH₂CF₃), —CH₂N(H)(C(O)CH(CH₃)₂), —CH₂N(H)(C(O)C(CH₃)₃), —CH₂N(H)(C(O)OCH₂CH₃), —CH₂N(H)(C(O)O-cyclopropyl), —CH₂N(H)(C(O)N(CH₃)₂), —CH₂N(H)(C(O)CH₂CN), —CH₂N(H)(C(O)CH₂OH), —CH₂N(H)(C(O)OCH₂CF₃), —CH₂N(H)(S(O)₂CH₂CH₃), —CH₂N(H)(S(O)₂CH₂CF₃) and —CH₂N(H)(S(O)₂-cyclopropyl).

In an embodiment of the compound of Formula Ia or Formula II, R² is selected from the group consisting of —CH₃, —CH₂OH, —CH₂F, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂CHF₂, —CH₂OCH₂CF₃, —CH₂OCH₂CH═CH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂—S(O)₂CH₃, —CH₂OC(O)OCH₃, —CH₂OC(O)OCH(CH₃)₂, —CH₂OC(O)OC(CH₃)₃, —CH₂OC(O)OCH₂CH₃, —CH₂OC(O)CH₃, —CH₂OC(O)C(CH₃)₃, —C(O)OH, —C(O)OCH₃, —CH₂OC(O)NH₂, —CH₂OC(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, and —CH₂N(CH₃)₂.

In an embodiment of the compound of Formula Ia or Formula II, R² is C₁-C₆-alkyl optionally substituted with 1, 2, or 3 halo groups. In an embodiment of the compound of Formula Ia or Formula II, R² is C₀-C₆-alkyl-OR⁶, wherein R⁶ is C₁-C₆-haloalkyl. In certain embodiments, R² is (CH₂)₁₋₂—O—C₁-C₃-alkyl, wherein C₁-C₃-alkyl is optionally substituted with 1, 2, or 3 halo groups. In certain embodiments, m is 1 or 2.

In an embodiment of the compound of Formula Ia or Formula II, n is 0, 1, or 2; and each R³ is independently C₁-C₆-alkyl.

In an embodiment of the compound of Formula Ia or Formula II, each R³ is independently C₁-C₃-alkyl. In a further embodiment of the compound of Formula I or Formula II, R³ is independently —CH₃.

In an embodiment of the compound of Formula Ia or Formula II, n is 1, and R³ is in the following position:

In an embodiment of the compound of Formula Ia or Formula II, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₅-heteroaryl, (CR^(a)R^(b))_(p)—C₆-aryl, or (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, wherein heteroaryl, aryl, and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is H or C₁-C₆-alkyl;

R^(b) is H or C₁-C₆-alkyl; and

p is 0 or 1.

In an embodiment of the compound of Formula I or Formula II, R² is selected from the group consisting of —CH₃, —CH₂OH, —CH₂F, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂CHF₂, —CH₂OCH₂CF₃, —CH₂OCH₂CH═CH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂—S(O)₂CH₃, —CH₂OC(O)OCH₃, —CH₂OC(O)OCH(CH₃)₂, —CH₂OC(O)OC(CH₃)₃, —CH₂OC(O)OCH₂CH₃, —CH₂OC(O)CH₃, —CH₂OC(O)C(CH₃)₃, —C(O)OH, —C(O)OCH₃, —CH₂OC(O)NH₂, —CH₂OC(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃,

—C(O)N(CH₃)₂, and —CH₂N(CH₃)₂. In an embodiment of the compound of Formula I or Formula II, n is 0, 1, or 2; and each R³ is independently C₁-C₆-alkyl. In an embodiment of the compound of Formula I or Formula II, each R³ is independently C₁-C₃-alkyl. In a further embodiment of the compound of Formula I or Formula II, R³ is independently —CH₃.

In another embodiment of the compound of Formula Ia or Formula II, R⁴ is C₁-C₅-heteroaryl, C₆-aryl, or C₃-C₇-cycloalkyl any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.

In an embodiment of the compound of Formula Ia or Formula II, R⁴ is phenyl, pyridinyl, or cyclohexyl, any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —F, —Br, —Cl, —I, —CN, —CH₃, —CH₂CH₃, —CF₃, —CHF₂, and —SF₅.

In an embodiment of the compound of Formula Ia or Formula II, R⁴ is selected from the group consisting of:

In an embodiment of the compound of Formula Ia or Formula II, R⁴ is selected from the group consisting of:

In an embodiment of the compound of Formula I or Formula II, R⁴ is (CR^(a)R^(b))_(p)—C₁-C₅-heteroaryl, (CR^(a)R^(b))_(p)—C₆-aryl, or (CR^(a)R^(b))_(p)—C₃-C₇-cycloalkyl, wherein heteroaryl, aryl, and cycloalkyl are optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(a) is H or C₁-C₆-alkyl;

R^(b) is H or C₁-C₆-alkyl; and

p is 0 or 1. In another embodiment of the compound of Formula I or Formula II, R⁴ is C₁-C₅-heteroaryl, C₆-aryl, or C₃-C₇-cycloalkyl, any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —OH, halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl. In an embodiment of the compound of Formula I or Formula II, R⁴ is phenyl, pyridinyl, or cyclohexyl, any of which is optionally substituted with 1, 2, or 3 groups, each independently selected from —F, —Br, —Cl, —I, —CN, —CH₃, —CH₂CH₃, —CF₃, —CHF₂, and —SF₅.

In an embodiment of the compound of Formula I or Formula II, R⁴ is selected from the group consisting of:

In another embodiment of the compound of Formula Ia or Formula II, R⁴ is

In another embodiment of the compound of Formula Ia or Formula II, R⁵ is H or —CH₃.

In an embodiment of the compound of Formula Ia or Formula II, R⁵ is H or C₁-C₆-alkyl. In an embodiment of the compound of Formula I or Formula II, R⁵ is H or C₁-C₆-alkyl. In another embodiment of the compound of Formula I or Formula II, R⁵ is H or —CH₃.

In another embodiment of the compound of Formula Ia,

A is N or C(H)

R¹ is C₁-C₆-alkyl;

R² is, independently selected from the group consisting of C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₀-C₆-alkyl-OR⁶, C₁-C₆-alkyl-N(R⁷)₂, C₀-C₆-alkyl-SR⁸, C₀-C₆-alkyl-S(O)R⁸, C₀-C₆-alkyl-S(O)₂R⁸, C₀-C₆-alkyl-C(O)OR⁹, C₀-C₆-alkyl-OC(O)R⁹, C₀-C₆-alkyl-OC(O)OR⁹, C₀-C₆-alkyl-OC(O)N(R⁷)₂, and C₀-C₆-alkyl-C(O)N(R⁷)₂;

R³ is, at each occurrence, independently selected from C₁-C₆-alkyl;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl and (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein the heteroaryl or aryl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁵ is H or C₁-C₆-alkyl;

R⁶ is selected from H, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkenyl, and C₀-C₆-alkyl-C₃-C₆-cycloalkyl;

R⁷ is selected from H, C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R⁸ is selected from H and C₁-C₆-alkyl;

R⁹ is selected from H and C₁-C₆-alkyl;

R^(a) is, at each occurrence, independently selected from H, —OH, halo, C₁-C₆-alkyl, C₁-C₆-haloalkyl, —O—C₁-C₆-alkyl, and C₁-C₆-alkyl-OH;

R^(b) is, at each occurrence, independently selected from H and C₁-C₆-alkyl;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0 or 1. In another embodiment of the compound of Formula Ia,

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —CH₂OH, —CH₂OCF₃, —C(O)-3,3-difluoroazetidine, —C(O)-3,3-difluoropyrrolidine, —C(O)N(CH₃)(CH₂CHF₂), —C(O)N(CH₃)(CH₂CF₃), —C(O)N(H)(CH₂CHF₂), —C(O)N(H)(CH₃), —C(O)N(H)(CH₂CF₃), —CH₂N(H)(C(O)CH₃), —CH₂N(H)(C(O)CF₃), —CH₂N(H)(C(O)OCH₃), —CH₂N(H)(S(O)₂CH₃), —CH₂N(H)(S(O)₂CF₃), —CH₂-pyrrolidin-2-one, —CH₂N(H)(C(O)CH₂CH₃), —CH₂N(H)(C(O)-cyclopropyl), —CH₂N(H)(C(O)CH₂CF₃), —CH₂N(H)(C(O)CH(CH₃)₂), —CH₂N(H)(C(O)C(CH₃)₃), —CH₂N(H)(C(O)OCH₂CH₃), —CH₂N(H)(C(O)O-cyclopropyl), —CH₂N(H)(C(O)N(CH₃)₂), —CH₂N(H)(C(O)CH₂CN), —CH₂N(H)(C(O)CH₂OH), —CH₂N(H)(C(O)OCH₂CF₃), —CH₂N(H)(S(O)₂CH₂CH₃), —CH₂N(H)(S(O)₂CH₂CF₃) and —CH₂N(H)(S(O)₂-cyclopropyl);

R³ is, at each occurrence, independently selected from C₁-C₆-alkyl;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl and (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein the heteroaryl or aryl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁵ is H;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0.

In further embodiment of the compound of Formula Ia,

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —CH_(3J)—CH₂OH, —CH₂F, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂CHF₂, —CH₂OCH₂CF₃, —CH₂OCH₂CH═CH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂—S(O)₂CH₃, —CH₂OC(O)OCH₃, —CH₂OC(O)OCH(CH₃)₂, —CH₂OC(O)OC(CH₃)₃, —CH₂OC(O)OCH₂CH₃, —CH₂OC(O)CH₃, —CH₂OC(O)C(CH₃)₃, —C(O)OH, —C(O)OCH₃, —CH₂OC(O)NH₂, —CH₂OC(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, and —CH₂N(CH₃)₂;

R³ is, at each occurrence, independently selected from C₁-C₆-alkyl;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl and (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein the heteroaryl or aryl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁵ is H;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0.

In another embodiment of the compound of Formula I,

R¹ is C₁-C₆-alkyl;

R² is, at each occurrence, independently selected from —CH_(3J)—CH₂OH, —CH₂F, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂CHF₂, —CH₂OCH₂CF₃, —CH₂OCH₂CH═CH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂—S(O)₂CH₃, —CH₂OC(O)OCH₃, —CH₂OC(O)OCH(CH₃)₂, —CH₂OC(O)OC(CH₃)₃, —CH₂OC(O)OCH₂CH₃, —CH₂OC(O)CH₃, —CH₂OC(O)C(CH₃)₃, —C(O)OH, —C(O)OCH₃, —CH₂OC(O)NH₂, —CH₂OC(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, and —CH₂N(CH₃)₂;

R³ is, at each occurrence, independently selected from C₁-C₆-alkyl;

R⁴ is selected from (CR^(a)R^(b))_(p)—C₁-C₉-heteroaryl and (CR^(a)R^(b))_(p)—C₆-C₁₂-aryl, wherein the heteroaryl or aryl is optionally substituted with 1, 2, 3, or 4 groups, each independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl;

R⁵ is H;

m is 0, 1 or 2;

n is 0, 1 or 2; and

p is 0.

In a particular embodiment, R¹ is methyl and R⁴ is 3-chloro-4-fluorophenyl.

In another particular embodiment, R¹ is methyl, R² is —CH₂OH and m is 1.

In yet another particular embodiment, R¹ is methyl, R² is —CH₂F and m is 1.

Provided herein are compounds according to the following embodiments:

In a particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R² is —CH₃, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, m is 1 and n is 0.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R² is —CH₃, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, m is 2 and n is 0.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R² is —CH₂F, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In another particular embodiment of Formula Ia, R¹ is C₁-C₆-alkyl, R² is —CH₂OCH₂CHF₂, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, n is 1, and R³ is C₁-C₆-alkyl.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl; R² is C₁-C₆-alkyl or C₀-C₆-alkyl-OR⁶, wherein alkyl is substituted with halo, and R⁶ is H or C₁-C₆-haloalkyl; R³ is C₁-C₆-alkyl; R⁴ is phenyl substituted with 1 or 2 groups, each independently selected from halo and —CN; R⁵ is H; m is 1; and n is 1.

In another particular embodiment of Formula I, R¹ is methyl; R² is —CH₂F or CH₂—O—CH₂CHF₂; R³ is methyl; R⁴ is phenyl substituted with 1 or 2 groups, each independently selected from F and —CN; R⁵ is H; m is 1; and n is 1.

In a particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂OH, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In a particular embodiment of Formula II, R¹ is —CD₃, R² is —CH₂OH, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂F, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂OCH₂CHF₂, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, —SF₅, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, n is 1, and R³ is C₁-C₆-alkyl.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂OH, R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂S(O)₂CH₃, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂OC(O)O—C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂OC(O)NH₂, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —C(O)NH₂, —C(O)NHCH₃, or —C(O)N(CH₃)₂, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂OC(O)N(CH₃)₂, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, m is 0 and n is 0.

In another particular embodiment of Formula I, R¹ is C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, m is 0 and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂F, R³ is C₁-C₆-alkyl, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is —CH₂N(CH₃)₂, R³ is C₁-C₆-alkyl, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl. In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is selected from —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH₂CH═CH₂, —CH₂OCH₂CH₂CH₃, —CH₂OCH₂-cyclopropyl, —CH₂OCH₂CHF₂, and —CH₂OCH₂CF₃, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another particular embodiment of Formula Ia, R¹ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, m is 0 and n is 0.

In another particular embodiment of Formula Ia, R¹ is C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl, R⁵ is H, m is 0 and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-OR⁶, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R⁶ is H, and n is 0.

In an embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-OR⁶, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R⁶ is C₁-C₆-haloalkyl, and n is 0.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(R⁷)₂, wherein two R⁷ groups together form a C₂-C₆ heterocycle with the N to which they are attached, wherein the C₂-C₆ heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(C₁-C₆-alkyl)(C₁-C₆-haloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(H)(C₁-C₆-haloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(H)(C₁-C₆-alkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(R⁷)₂, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, wherein two R⁷ groups together form a C₂-C₆ heterocycle with the N to which they are attached, wherein the C₂-C₆ heterocycle is further independently and optionally substituted with 1 or 2 oxo or halogen substituents and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(C₁-C₆-alkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(C₁-C₆-haloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)C₁-C₆-alkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)C₁-C₆-haloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)C₁-C₆-alkyl-OH), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)C₁-C₆-alkyl-CN), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)C₃-C₇-cycloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)O—C₁-C₆-alkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)O—C₁-C₆-haloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)O—C₃-C₇-cycloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—C(O)N(C₁-C₆-alkyl)₂), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—S(O)₂C₁-C₆-alkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—S(O)₂C₁-C₆-haloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(H)(—S(O)₂C₃-C₇-cycloalkyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R⁷ is —S(O)₂C₃-C₇-cycloalkyl, and H, and n is 0.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is selected from —CH₂OH, —CH₂OCF₃, —C(O)-3,3-difluoroazetidine, —C(O)-3,3-difluoropyrrolidine, —C(O)N(CH₃)(CH₂CHF₂), —C(O)N(CH₃)(CH₂CF₃), —C(O)N(H)(CH₂CHF₂), —C(O)N(H)(CH₃), —C(O)N(H)(CH₂CF₃), —CH₂N(H)(C(O)CH₃), —CH₂N(H)(C(O)CF₃), —CH₂N(H)(C(O)OCH₃), —CH₂N(H)(S(O)₂CH₃), —CH₂N(H)(S(O)₂CF₃), —CH₂-pyrrolidin-2-one, —CH₂N(H)(C(O)CH₂CH₃), —CH₂N(H)(C(O)-cyclopropyl), —CH₂N(H)(C(O)CH₂CF₃), —CH₂N(H)(C(O)CH(CH₃)₂), —CH₂N(H)(C(O)C(CH₃)₃), —CH₂N(H)(C(O)OCH₂CH₃), —CH₂N(H)(C(O)O-cyclopropyl), —CH₂N(H)(C(O)N(CH₃)₂), —CH₂N(H)(C(O)CH₂CN), —CH₂N(H)(C(O)CH₂OH), —CH₂N(H)(C(O)OCH₂CF₃), —CH₂N(H)(S(O)₂CH₂CH₃), —CH₂N(H)(S(O)₂CH₂CF₃) and —CH₂N(H)(S(O)₂-cyclopropyl), R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 0.

In an embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-OR⁶, R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R⁶ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(C₁-C₆-haloalkyl)(C₁-C₆-alkyl), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(C₁-C₆-haloalkyl)(H), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₀-C₆-alkyl-C(O)N(C₁-C₆-alkyl)(H), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(—C(O)C₁-C₆-alkyl)(H), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(—S(O)₂C₁-C₆-alkyl)(H), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In yet another embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is C₁-C₆-alkyl-N(—C(O)O—C₁-C₆-alkyl)(H)), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In another particular embodiment of Formula II, R¹ is C₁-C₆-alkyl, R² is selected from —CH₂OH, —C(O)N(CH₃)(CH₂CHF₂), —C(O)N(H)(CH₂CHF₂), —C(O)N(H)(CH₃), —CH₂N(H)(C(O)CH₃), —CH₂N(H)(C(O)OCH₃), —CH₂N(H)(S(O)₂CH₃), R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, and nisi. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R^(c) is H, C₁₋₄alkyl, CH₂CH═CH₂, CH₃CHF₂, CH₂CH₂OH, CH₂CH₂CH₂OH, or CH₂CH(OH)CH₃, m is 0, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is selected from —C₁₋₄haloalkyl, OH, C₁₋₄alkyl, CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, CH(OH)cyclopropyl, CH₂OCH₂CHF₂, R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R^(c) is H, C₁₋₄alkyl, CH₂CH═CH₂, CH₃CHF₂, CH₂CH₂OH, CH₂CH₂CH₂OH, CH₂CH(OH)CH₃, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R^(c) is absent, m is 0, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

In an embodiment of Formula III, R¹ is C₁-C₆-alkyl, R² is selected from —C₁₋₄haloalkyl, OH, C₁₋₄alkyl, CH₂OH, CH(OH)CH₃, CH(OH)CH₂CH₃, CH(OH)cyclopropyl, CH₂OCH₂CHF₂, R³ is C₁-C₆-alkyl, R⁴ is phenyl, wherein the phenyl is substituted with at least one halogen, R⁵ is H, R^(c) is absent, and n is 1. In a more particular embodiment, R³ is (R)-methyl.

Certain embodiments of Formulas I and II are shown below in Table 1.

TABLE 1

001

002

003

004

005

006

007

008

009

010

011

012

013

014

015

016

017

018

019

020

021

022

023

024

025

026

027

028

029

030

031

106

032

033

034

035

107

036

037

038

039

040

041

042

043

044

045

046

047

048

049

050

051

052

053

054

055

056

057

058

059

060

061

062

063

064

065

066

067

068

069

070

071

072

073

074

075

076

077

078

079

080

081

082

083

084

085

086

087

088

089

090

091

092

093

094

095

096

097

098

099

100

101

102

103

104

105

In an embodiment, compounds of Formulas I and II are selected from:

Compound ID Compound Name 001 N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 002 4-(hydroxymethyl)-2-methyl-1-oxo-N-(m-tolyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 003 N-(2-chloro-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 004 N-(3-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 005 N-(3,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 006 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3,4,5-trifluorophenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 007 N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 008 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 009 N-(3-ethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 010 N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 011_E1 (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 011_E2 (R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 012 N-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 013 N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 014 N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 015 N-(3-bromo-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 016 N-(2,5-dimethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 017 N-(5-bromo-2-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5][oxadiazepine-10(2H)-carboxamide 018 N-(5-bromo-4-fluoro-2-methylphenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 019 4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 020 4-(hydroxymethyl)-N-(3-iodophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 021 N-(3-(difluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 022 N-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)- 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 023 N-(2,3-dichloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 024 N-(3,4-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 025 N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 026 N-(3-chloro-4-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 027 N-(4,5-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 028_E1 (S*)N(3-chloro-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 029 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(pentafluoro-16- sulfanyl)phenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 030 N-(3-chlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 031_E1 (S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 031_E2 (R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 032_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 033_E1 (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 034_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 035_E1 (S*)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 036 4-(fluoromethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 037_E1 (S*)-N-(3-chlorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 038_E1 (S*)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 039_E1 (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 040_E1 (S*)N(3-bromo-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 041_E1 (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(fluoromethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 042_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 043_E1 (S*)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 044_E1 (S*)-N-(3-chloro-4,5-difluorophenyl)-4-(fluoromethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 045 N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N,2-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 046 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 047 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 048 N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1 - oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 049_E1 (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 049_E2 (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 049_E3 (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 049_E4 (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)- methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 050 N-(3-chloro-4-fluorophenyl)-2-methyl-4-((methylsulfonyl)methyl)-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 051 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl methyl carbonate 052 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl acetate 053 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl isopropyl carbonate 054 tert-butyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1- oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl) carbonate 055 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl pivalate 056 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl ethyl carbonate 057 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo- 1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepin-4-yl)methyl carbamate 058 N-(3-chloro-4-fluoro-phenyl)-4- [(dimethylamino)methyl]-2-methyl- 1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10-carboxamide 059 [10-[(3-chloro-4-fluoro -phenyl)carbamoyl]-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepin-4-yl]methyl N,N-dimethylcarbamate 060_E1 (S*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 060_E2 (R*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo- 1,4,5,8, 9, 11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 061 N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 062 N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 063 N-(3-chlorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadeizepine- 10(2H)-carboxamide 064 N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-5,8,9,11- tetrahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 065 N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-methyl -1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 066 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide 067 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide 068 N-(3 -chloro-4-fluoro-phenyl)- 1 -oxo-2- propyl -5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide 069_E1 (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 069_E2 (4R*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 069_E3 (4R*,9R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 069_E4 (4S*,9R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 070 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)- 2,9-dimethyl-1- oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 071 methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-4-carboxylate 072 N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- dicarboxamide 073 N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo -5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- dicarboxamide 074 N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10- dicarboxamide 075 (9R)-N-(3 -chloro-4-fluoro-phenyl)-2,9-dimethyl- 1 -oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10- carboxamide 076 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 077 (R)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 078 (R)-N-(2-bromo-3-fluoropyridin-4-yl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 079 (R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 080 (R)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 081 (R)-N-(3-chloro-4,5-difluorophenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 082_E1 (4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 082_E2 (4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 083_E1 (4S*,9R)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 083_E2 (4R*,9R)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 084_E1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 084_E2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 085_E1 (4S*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)- 2,9-dimethyl-l-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 085_E2 (4R*,9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 086_E1 (4S*,9R)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 086_E2 (4R*,9R)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 087_E1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 087_E2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 088_E1 (4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 088_E2 (4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 089_E1 (4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 089_E2 (4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 090_E1 (4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 090_E2 (4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 091_E1 (4S*,9R)-N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 091_E2 (4R*,9R)-N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 092_E1 (4S*,9R)-N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 092_E2 (4R*,9R)-N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 093_D1 (4S*,9R)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 093_D2 (4R*,9R)-N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 094_D1 (4S*,9R)-N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 094_D2 (4R*,9R)-N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 095_D1 (4S*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4- ((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 095_D2 (4R*,9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4- ((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 096_D1 (4S*,9R)-N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 096_D2 (4R*,9R)-N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 097_D1 (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 097_D2 (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)- 2,9-dimethyl-1-oxo-1,4,5, 8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 098_D1 (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine 10(2H)-carboxamide 098_D2 (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3 - (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine 10(2H)-carboxamide 099_D1 (4S*,9R)-N-(5-chloro-2,4-difluorophenyl)-4- ((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5, 8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 099_D2 (4R*,9R)-N-(5-chloro-2,4-difluorophenyl)-4- ((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5, 8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 100_D1 (4S*,9R)-N-(5-bromo-2,4-difluorophenyl)-4- ((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5, 8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 100_D2 (4R*,9R)-N-(5-bromo-2,4-difluorophenyl)-4- ((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5, 8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 101 N-(3-chloro-4-fluoro-phenyl) -4-(ethoxymethyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 102 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 103 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(propoxymethyl)- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 104 N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropylmethoxymethyl)-2- methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 105 N-(3-chloro-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2- methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10(2H)-carboxamide 106 N-(3-chloro-4-fluoro-phenyl)-2- methyl-1-oxo-4-(2,2,2- trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 107 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-2- (trideuteriomethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4- d][1,2,5]oxadiazepine-10-carboxamide *Pure but unknown enantiomer or diastereomer. and pharmaceutically acceptable salts thereof.

Certain embodiments of Formulae I and II are shown below in Table 2.

TABLE 2

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

In an embodiment, compounds of Formulae I and II are selected from:

Com- pound ID Compound Name 108_D1 (4S*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 108_D2 (4R*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 109_D1 (4S*, 9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 109_D2 (4S*, 9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 109_D3 (4R*, 9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 109_D4 (4R*, 9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 110_D1 (4S*, 9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide CompoundIDCompoundName 110_D2 (4R*, 9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 111_D1 (4S*, 9R)-N10-(5-chloro-24-difluorophenyl)-N429-trimethyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 111_D2 (4R*, 9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9- trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 112_D1 (4S*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 112_D2 (4R*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 113 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1- oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 114_E1 (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl- 1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-10-carboxamide 115_D1 (4S*, 9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 115_D2 (4R*, 9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 116_D1 (4S*, 9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl) phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 116_D2 (4R*, 9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl) phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-[1,2,5]oxadiazepine-10(2H)- carboxamide 117_D1 (4S*, 9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 117_D2 (4R*, 9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 118 N10-(3-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 119 N10-(5-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 120 N10-(3-cyano-4-fluorophenyl)-N4,2-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] doxadiazepine-4,10(2H)-icarboxamide 121_D1 (4S*, 9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 121_D2 (4R*, 9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 122_D1 (4S*, 9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 122_D2 (4R*, 9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 123_D1 (4S*, 9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 123_D2 (4R*, 9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 124_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 124_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 125_D1 (4S*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 125_D2 (4R*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 126_D1 (4S*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 126_D2 (4R*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 127_D1 (4S*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 127_D2 (4R*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4-((2,2- difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide *Pure but unknown enantiomer or diastereomer. and pharmaceutically acceptable salts thereof.

Certain embodiments of Formula Ia and Formula II are shown below in Table 3.

TABLE 3

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

In an embodiment, compounds of Formulas Ia and II are selected from:

Com- pound ID Compound Name 128 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4- (trifluoromethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 129 N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 130 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(((2,2,2- trifluoroethyl)sulfonamido)methyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 131 N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoroazetidine-1- carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 132 N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoropyrrolidine-1- carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 133 N10-(3-chloro-4-fluorophenyl)-N4,2-dimethyl-1-oxo-N4- (2,2,2-trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 134 N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 135 N10-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-N4-(2,2,2- trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 136 N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 137_E1 (S*)-N-(3-chloro-2,4,5-trifluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 138_E1 (S*)-N-(3-chloro-2,6-difluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 139_E1 (S*)-N-(5-chloro-2-fluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 140_E1 (S*)-N-(5-bromo-2,3-difluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 141_E1 (S*)-N-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 142_E1 (S*)-N-(2,4-difluoro-3-methylphenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 143_E1 (S*)-N-(2,4-difluoro-5-methylphenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 144_E1 (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,4,5-trifluoro-3- methylphenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 145_E1 (S*)-N-(5-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 146_E1 (S*)-N-(3-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 147_E1 (S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 148_E1 (S*)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 149_E1 (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4- (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 150_E1 (S*)-N-(2-bromo-5-fluoropyridin-4-yl)-4-(hydroxymethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 151_E1 (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,3,4,5- tetrafluorophenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 152_D1 (4S*, 9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 152_D2 (4R*, 9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 153_D1 (4S*, 9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 153_D2 (4R*, 9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 154_D1 (4S*, 9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 154_D2 (4R*, 9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 155_D1 (4S*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 155_D2 (4R*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2- difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 4,10(2H)-dicarboxamide 156_D1 (4S*, 9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-,410(2H)-dicarboxamide 156_D2 (4R*, 9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 157_D1 (4S*, 9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4- (hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 157_D2 (4R*, 9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]-4- (hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 158 N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)- N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 159 N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)- N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 160 N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2- dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 161 N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4, 2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 162 4-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide 163 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2- trifluoroacetamido)methyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 164 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- (((trifluoromethyl)sulfonamido)methyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 165 N-(3-chloro-4-fluorophenyl)-2-methyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 166 methyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate 167_E1 (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-difluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 168_E1 (S*)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 169_E1 (S*)-4-(acetamidomethyl)-N-(3-chloro-2,4-difluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 170_E1 (S*)-4-(acetamidomethyl)-N-(3-bromo-2,4-difluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 171_E1 (S*)-4-(acetamidomethyl)-N-(3-bromo-4-fluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 172_E1 (S*)-4-(acetamidomethyl)-N-(2,4-difluoro-3-(trifluoromethyl) phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 173_E1 (S*)-4-(acetamidomethyl)-N-(5-chloro-2,4-difluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 174_E1 (S*)-4-(acetamidomethyl)-N-(5-bromo-2,4-difluorophenyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 175_E1 (S*)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl) phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 176_D1 (4S*, 9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 176_D2 (4R*, 9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)- 2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 177_D1 (4S*, 9R)-4-(acetamidomethyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 177_D2 (4R*, 9R)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl) phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 178_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 178_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4- (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 179_D1 (4S*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl- 4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 179_D2 (4R*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9- dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 180_D1 methyl (((4S*, 9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)- 2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl) carbamate 180_D2 methyl (((4R*, 9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)- 2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl) carbamate 181_D1 methyl(((4S*, 9R)-10-((4-fluoro-3-(trifluoromethyl)phenyl) carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11- octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4- yl)methyl)carbamate 181_D2 methyl (((4R*, 9R)-10-((4-fluoro-3-(trifluoromethyl)phenyl) carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11- octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4- yl)methyl)carbamate 182_D1 (4S*, 9R)-4(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 182_D2 (4R*, 9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 183_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl) amino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 183_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethyl) amino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 184_D1 (4S*, 9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2- difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 184_D2 (4R*, 9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethyl) amino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 185_D1 (4S*, 9R)-4-((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 185_D2 (4R*, 9R)-4-((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 186_E1 (S*)-N-(3-cyano-2,4-difluorophenyl)-4-((2,2-difluoroethyl) amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 187_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethyl)amino) methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 188_E1 (S*)-N-(3-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethyl) amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 189_E1 (S*)-N-(3-bromo-2,4-difluorophenyl)-4-((2,2-difluoroethyl) amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 190_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino) methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 191_E1 (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-((2,2- difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 192_E1 (S*)-N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethyl) amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 193_E1 (S*)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 194_E1 (S*)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 195 N10-(3-cyano-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 196 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-[(2- oxopyrrolidin-1-yl)methyl]-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 197 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- (propionamidomethyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 198 N-(3-chloro-4-fluorophenyl)-4- (cyclopropanecarboxamidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 199 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((3,3,3- trifluoropropanamido)methyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 200 N-(3-chloro-4-fluorophenyl)-4-(isobutyramidomethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 201 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- (pivalamidomethyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 202 ethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1- oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate 203 cyclopropyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2- methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate 204 N-(3-chloro-4-fluorophenyl)-4-((3,3-dimethylureido)methyl)- 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 205 N-(3-chloro-4-fluorophenyl)-4-((2-cyanoacetamido)methyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 206 N-(3-chloro-4-fluorophenyl)-4-((2-hydroxyacetamido)methyl)- 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 207 2,2,2-trifluoroethyl((10-((3-chloro-4-fluorophenyl)carbamoyl)- 2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate 208 N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2- methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 209 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-4,5,8,9,10,11-hexahydro-[1,2,5]oxadiazepino[5,4-b] indazole-10-carboxamide and pharmaceutically acceptable salts thereof.

Certain embodiments of Formula Ia are shown below in Table 4.

TABLE 4

210

211

212

213

214

In an embodiment, compounds of Formula Ia are selected from:

Com- pound ID Compound Name 210 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-4- ((2,2,2-trifluoroethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 211 (S*)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 212 (S*)-4((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 213 (R)-N-(3-cyano-4-fluorophenyl)-2,4,4,9-tetramethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 214 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,4,4,9-tetramethyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]oxadiazepine-10(2H)-carboxamide *Pure but unknown enantiomeror diastereomer. and pharmaceutically acceptable salts thereof.

Certain embodiments of Formula III are shown below in Table 5.

TABLE 5

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

In an embodiment, compounds of Formula III are selected from:

Com- pound ID Compound Name 216 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 217 N-(3-chloro-4-fluorophenyl)-2,3-dimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 218 (R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 219 (R)-N-(3-cyano-4-fluorophenyl)-3-(2,2-difluoroethyl)-2,9- dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 220 (R)-N-(3-cyano-4-fluorophenyl)-3-(2-hydroxyethyl)-2,9- dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 221 (R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-propyl- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 222 (R)-N-(3-cyano-4-fluorophenyl)-3-(3-hydroxypropyl)-2,9- dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 223 (9R)-N-(3-cyano-4-fluorophenyl)-3-(2-hydroxypropyl)-2,9- dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 224 (R)-N-(3-cyano-4-fluorophenyl)-2,3,9-trimethyl-1-oxo- 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 225 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,3,9-trimethyl-1- oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 226 N-(3-chloro-4-fluorophenyl)-4-hydroxy-2-methyl-1-oxo-4- (trifluoromethyl)-1,2,3,4,5,8,9,11-octahydro-10H-pyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 227 N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 228 N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1- oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 229 N-(3-chloro-4-fluorophenyl)-4-(1-hydroxypropyl)-2-methyl- 1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 230 N-(3-chloro-4-fluorophenyl)-4-(1-hydroxyethyl)-2-methyl-1- oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]triazepine-10-carboxamide 231 N-(3-chloro-4-fluorophenyl)-4-(cyclopropyl(hydroxy)methyl)- 2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 232 N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide 233 (R)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 234 (R)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 235 (R)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9- dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 236 (R)-N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 237 (R)-N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy) methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10- carboxamide 238 (R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] triazepine-10-carboxamide *Pure but unknown enantiomer or diastereomer. and pharmaceutically acceptable salts thereof.

The disclosed compounds may possess one or more stereocenters, and each stereocenter may exist independently in either the R or S configuration. In one embodiment, compounds described herein are present in optically active or racemic forms. It is to be understood that the compounds described herein encompass racemic, optically-active, regioisomeric and stereoisomeric forms, or combinations thereof that possess the therapeutically useful properties described herein.

Preparation of optically active forms is achieved in any suitable manner, including by way of non-limiting example, by resolution of the racemic form with recrystallization techniques, synthesis from optically-active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase. In one embodiment, a mixture of one or more isomer is utilized as the disclosed compound described herein. In another embodiment, compounds described herein contain one or more chiral centers. These compounds are prepared by any means, including stereoselective synthesis, enantioselective synthesis or separation of a mixture of enantiomers or diastereomers. Resolution of compounds and isomers thereof is achieved by any means including, by way of non-limiting example, chemical processes, enzymatic processes, fractional crystallization, distillation, and chromatography.

In one embodiment, the disclosed compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

Compounds described herein also include isotopically-labeled compounds wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds described herein include and are not limited to ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, and ³⁵S. In one embodiment, isotopically-labeled compounds are useful in drug or substrate tissue distribution studies. In another embodiment, substitution with heavier isotopes such as deuterium affords greater metabolic stability (for example, increased in vivo half-life or reduced dosage requirements).

In yet another embodiment, substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, is useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds are prepared by any suitable method or by processes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

In one embodiment, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

The compounds described herein, and other related compounds having different substituents are synthesized using techniques and materials described herein and as described, for example, in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley 1999) (all of which are incorporated by reference for such disclosure). General methods for the preparation of compound as described herein are modified by the use of appropriate reagents and conditions, for the introduction of the various moieties found in the formula as provided herein.

Compounds described herein are synthesized using any suitable procedures starting from compounds that are available from commercial sources, or are prepared using procedures described herein.

Methods

Provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Also provided herein is a method of eradicating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of reducing viral load associated with an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Further, provided herein is a method of reducing reoccurrence of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

In certain aspects, the methods and/or compositions described herein are effective for inhibiting or reducing the formation or presence of HBV-associated particles in vitro or in vivo (e.g., in a cell, in a tissue, in an organ (e.g., in the liver), in an organism or the like). HBV-associated particles may contain HBV DNA (i.e., linear and/or covalently closed circular DNA (cccDNA)) and/or HBV RNA (i.e., pre-genomic RNA and/or sub-genomic RNA). Accordingly, HBV-associated particles include HBV DNA-containing particles or HBV RNA-containing particles.

As used herein, “HPV-associated particles” refer to both infectious HBV virions (i.e., Dane particles) and non-infectious HBV subviral particles (i.e., HBV filaments and/or HBV spheres). HBV virions comprise an outer envelope including surface proteins, a nucleocapsid comprising core proteins, at least one polymerase protein, and an HBV genome. HBV filaments and HBV spheres comprise HBV surface proteins, but lack core proteins, polymerase and an HBV genome. HBV filaments and HBV spheres are also known collectively as surface antigen (HBsAg) particles. HBV spheres comprise middle and small HBV surface proteins. HBV filaments also include middle, small and large HBV surface proteins.

HBV subviral particles can include the nonparticulate or secretory HBeAg, which serves as a marker for active replication of HBV.

Provided herein is a method of reducing an adverse physiological impact of an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Also provided herein is a method of reducing, slowing, or inhibiting an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of inducing reversal of hepatic injury from an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of reducing the physiological impact of long-term antiviral therapy for HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

Provided herein is a method of prophylactically treating an HBV infection in an individual in need thereof, wherein the individual is afflicted with a latent HBV infection, comprising administering to the individual a therapeutically effective amount of a disclosed compound.

In one embodiment, the individual is refractory to other therapeutic classes of HBV drugs (e.g, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, antiviral compounds of distinct or unknown mechanism, and the like, or combinations thereof). In another embodiment, the disclosed method reduces viral load in an individual suffering from an HBV infection to a greater extent or at a faster rate compared to the extent that other therapeutic classes of HBV drugs reduce viral load in the individual.

In one embodiment, the administering of a disclosed compound, or a pharmaceutically acceptable salt thereof, allows for administering of the at least one additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.

In one embodiment, the administering of a disclosed compound, or a pharmaceutically acceptable salt thereof, reduces the viral load in the individual to a greater extent or at a faster rate compared to the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and any combination thereof.

In one embodiment, the disclosed method reduces viral load in an individual suffering from an HBV infection, thus allowing lower doses or varying regimens of combination therapies to be used.

In one embodiment, the disclosed method causes a lower incidence of viral mutation or viral resistance compared to other classes of HBV drugs, thereby allowing for long term therapy and minimizing the need for changes in treatment regimens.

In one embodiment, the administering of a compound the invention, or a pharmaceutically acceptable salt thereof, causes a lower incidence of viral mutation or viral resistance than the administering of a compound selected from the group consisting of an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.

In one embodiment, the disclosed method increases the seroconversion rate from HBV infected to non-HBV infected or from detectable HBV viral load to non-detectable HBV viral load beyond that of current treatment regimens. As used herein, “seroconversion” refers to the period of time during which HBV antibodies develop and become detectable.

In one embodiment, the disclosed method increases or normalizes or restores normal health, elicits full recovery of normal health, restores life expectancy, or resolves the viral infection in the individual in need thereof.

In one embodiment, the disclosed method eliminates or decreases the number of HBV RNA particles that are released from HBV infected cells thus enhancing, prolonging, or increasing the therapeutic benefit of the disclosed compounds.

In one embodiment, the disclosed method eradicates HBV from an individual infected with HBV, thereby obviating the need for long term or life-long treatment, or shortening the duration of treatment, or allowing for reduction in dosing of other antiviral agents.

In another embodiment, the disclosed method further comprises monitoring or detecting the HBV viral load of the subject, and wherein the method is carried out for a period of time including until such time that the HBV virus is undetectable.

Accordingly, in one embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula Ia, or a pharmaceutically acceptable salt thereof.

Accordingly, in one embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula II, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Formula III, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 1, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 2, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 3, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 4, or a pharmaceutically acceptable salt thereof.

In another embodiment, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of Table 5, or a pharmaceutically acceptable salt thereof.

In an embodiment of any of the methods provided herein, the method can further comprise monitoring the HBV viral load of the subject, wherein the method is carried out for a period of time such that the HBV virus is undetectable.

Combination Therapies

The disclosed compounds may be useful in combination with one or more additional compounds useful for treating HBV infection. These additional compounds may comprise other disclosed compounds and/or compounds known to treat, prevent, or reduce the symptoms or effects of HBV infection. Such compounds include, but are not limited to, HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly modulators, reverse transcriptase inhibitors, immunomodulatory agents, TLR-agonists, and other agents with distinct or unknown mechanisms that affect the HBV life cycle or affect the consequences of HBV infection.

In non-limiting examples, the disclosed compounds may be used in combination with one or more drugs (or a salt thereof) selected from the group comprising: HBV reverse transcriptase inhibitors, and DNA and RNA polymerase inhibitors including, but not limited to, lamivudine (3TC, Zeffix, Heptovir, Epivir, and Epivir-HBV), entecavir (Baraclude, Entavir), adefovir dipivoxil (Hepsara, Preveon, bis-POM PMEA), tenofovir disoproxil fumarate (Viread, TDF or PMPA);

interferons including, but not limited to, interferon alpha (IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ);

viral entry inhibitors;

viral maturation inhibitors;

literature-described capsid assembly modulators, such as, but not limited to, BAY 41-4109;

reverse transcriptase inhibitors;

immunomodulatory agents such as TLR-agonists; and

agents of distinct or unknown mechanisms, such as but not limited to AT-61 ((E)-N-(1-chloro-3-oxo-1-phenyl-3-(piperidin-1-yl)prop-1-en-2-yl)benzamide), AT-130 ((E)-N-(1-bromo-1-(2-methoxyphenyl)-3-oxo-3-(piperidin-1-yl)prop-1-en-2-yl)-4-nitrobenzamide), and similar analogs.

In one embodiment, the additional therapeutic agent is an interferon. The term “interferon” or “IFN” refers to any member of the family of highly homologous species-specific proteins that inhibit viral replication and cellular proliferation and modulate immune response. Human interferons are grouped into three classes: Type I, which includes interferon-alpha (IFN-α), interferon-beta (IFN-β), and interferon-omega (IFN-ω), Type II, which includes interferon-gamma (TFN-γ), and Type III, which includes interferon-lambda (IFN-λ). Recombinant forms of interferons that have been developed and are commercially available are encompassed by the term “interferon” as used herein. Subtypes of interferons, such as chemically modified or mutated interferons, are also encompassed by the term “interferon” as used herein. Chemically modified interferons may include pegylated interferons and glycosylated interferons. Examples of interferons also include, but are not limited to, interferon-alpha-2a, interferon-alpha-2b, interferon-alpha-n1, interferon-beta-1a, interferon-beta-1b, interferon-lambda-1, interferon-lambda-2, and interferon-lambda-3. Examples of pegylated interferons include pegylated interferon-alpha-2a and pegylated interferon alpha-2b.

Accordingly, in one embodiment, the compounds of Formula Ia, Formula I, or Formula II can be administered in combination with an interferon selected from the group consisting of interferon alpha (IFN-α), interferon beta (IFN-β), interferon lambda (IFN-λ), and interferon gamma (IFN-γ). In one specific embodiment, the interferon is interferon-alpha-2a, interferon-alpha-2b, or interferon-alpha-n1. In another specific embodiment, the interferon-alpha-2a or interferon-alpha-2b is pegylated. In a preferred embodiment, the interferon-alpha-2a is pegylated interferon-alpha-2a (PEGASYS).

In another embodiment, the additional therapeutic agent is selected from immune modulator or immune stimulator therapies, which includes biological agents belonging to the interferon class.

Further, the additional therapeutic agent may be an agent of distinct or unknown mechanism including agents that disrupt the function of other essential viral protein(s) or host proteins required for HBV replication or persistence.

In another embodiment, the additional therapeutic agent is an antiviral agent that blocks viral entry or maturation or targets the HBV polymerase such as nucleoside or nucleotide or non-nucleos(t)ide polymerase inhibitors. In a further embodiment of the combination therapy, the reverse transcriptase inhibitor or DNA or RNA polymerase inhibitor is Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In an embodiment, the additional therapeutic agent is an immunomodulatory agent that induces a natural, limited immune response leading to induction of immune responses against unrelated viruses. In other words, the immunomodulatory agent can effect maturation of antigen presenting cells, proliferation of T-cells and cytokine release (e.g., IL-12, IL-18, IFN-alpha, -beta, and -gamma and TNF-alpha among others),

In a further embodiment, the additional therapeutic agent is a TLR modulator or a TLR agonist, such as a TLR-7 agonist or TLR-9 agonist. In further embodiment of the combination therapy, the TLR-7 agonist is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine) and AZD 8848 (methyl [3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino}methyl)phenyl]acetate).

In any of the methods provided herein, the method may further comprise administering to the individual at least one HBV vaccine, a nucleoside HBV inhibitor, an interferon or any combination thereof. In an embodiment, the HBV vaccine is at least one of RECOMB IV AX HB, ENGERIX-B, ELOVAC B, GENEVAC-B, or SHANVAC B.

In one embodiment, the methods described herein further comprise administering at least one additional therapeutic agent selected from the group consisting of nucleotide/nucleoside analogs, entry inhibitors, fusion inhibitors, and any combination of these or other antiviral mechanisms.

In another aspect, provided herein is method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a disclosed compound alone or in combination with a reverse transcriptase inhibitor; and further administering to the individual a therapeutically effective amount of HBV vaccine. The reverse transcriptase inhibitor may be at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.

In another aspect, provided herein is a method of treating an HBV infection in an individual in need thereof, comprising reducing the HBV viral load by administering to the individual a therapeutically effective amount of a disclosed compound alone or in combination with a antisense oligonucleotide or RNA interference agent that targets HBV nucleic acids; and further administering to the individual a therapeutically effective amount of HBV vaccine. The antisense oligonucleotide or RNA interference agent possesses sufficient complementarity to the the target HBV nucleic acids to inhibit replication of the viral genome, transcription of viral RNAs, or translation of viral proteins.

In another embodiment, the disclosed compound and the at least one additional therapeutic agent are co-formulated. In yet another embodiment, the disclosed compound and the at least one additional therapeutic agent are co-administered.

For any combination therapy described herein, synergistic effect may be calculated, for example, using suitable methods such as the Sigmoid-E_(max) equation (Holford & Scheiner, 19981, Clin. Pharmacokinet. 6: 429-453), the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22: 27-55). Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination. The corresponding graphs associated with the equations referred to above are the concentration-effect curve, isobologram curve and combination index curve, respectively.

In an embodiment of any of the methods of administering combination therapies provided herein, the method can further comprise monitoring or detecting the HBV viral load of the subject, wherein the method is carried out for a period of time including until such time that the HBV virus is undetectable.

Administration/Dosage/Formulations

In another aspect, provided herein is a pharmaceutical composition comprising at least one disclosed compound, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

In particular, the selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds or materials used in combination with the compound, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts.

A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could begin administration of the pharmaceutical composition to dose the disclosed compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In particular embodiments, it is especially advantageous to formulate the compound in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of the disclosed compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the disclosed compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding/formulating such a disclosed compound for the treatment of HBV infection in a patient.

In one embodiment, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier.

In some embodiments, the dose of a disclosed compound is from about 1 mg to about 2,500 mg. In some embodiments, a dose of a disclosed compound used in compositions described herein is less than about 10,000 mg, or less than about 8,000 mg, or less than about 6,000 mg, or less than about 5,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound (i.e., another drug for HBV treatment) as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof.

In one embodiment, the present invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a disclosed compound, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of HBV infection in a patient.

Routes of administration of any of the compositions of the invention include oral, nasal, rectal, intravaginal, parenteral, buccal, sublingual or topical. The compounds for use in the invention may be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

For oral application, particularly suitable are tablets, dragees, liquids, drops, suppositories, or capsules, caplets and gelcaps. The compositions intended for oral use may be prepared according to any method known in the art and such compositions may contain one or more agents selected from the group consisting of inert, non-toxic pharmaceutically excipients that are suitable for the manufacture of tablets. Such excipients include, for example an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay the release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert diluent.

For parenteral administration, the disclosed compounds may be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing or dispersing agents may be used.

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including but not limited to reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

The following examples further illustrate aspects of the present invention. However, they are in no way a limitation of the teachings or disclosure of the present invention as set forth herein.

EXAMPLES

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Unless otherwise specified, the variables are as defined above in reference to Formula (Ia). Reactions may be performed between the melting point and the reflux temperature of the solvent, and preferably between 0° C. and the reflux temperature of the solvent. Reactions may be heated employing conventional heating or microwave heating. Reactions may also be conducted in sealed pressure vessels above the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

TABLE 6 Term Acronym Acetonitrile ACN or MeCN Aqueous aq Atmosphere atm tert-Butylcarbamoyl Boc Boron-dipyrromethene BODIPY Benzyl Bn Broad br Capside assembly CA Carboxybenzyl CBz Diatomaceous Earth Celite ® 1,1′-Carbonyldiimidazole CDI Doublet of doublets dd Diethylaminosulfur trifluoride DAST Di-tert-butyl azodicarboxylate DBAD 1,8-Diazabicyclo[5.4.0]undec-7-ene DBU Dichloroethane DCE Dichloromethane DCM Bis(2-methoxyethyl)aminosulfur trifluoride Deoxo-Fluor ® Diethyl azodicarboxylate DEAD Diisopropyl azodicarboxylate DIAD Diisopropylethylamine DIPEA, DIEA, or Hunig's base 4-Dimethylaminopyridine DMAP 1,2-Dimethoxyethane DME N,N-Dimethylformamide DMF Dimethyl sulfide DMS Dimethylsulfoxide DMSO Deoxyribonucleic Acid DNA 1-Ethyl-3-(3-dimethylaminopropyl) EDCI, EDAC, carbodiimide or EDC Diethyl ether Ether, Et₂O Ethyl Acetate EtOAc, or EA Ethanol EtOH Electrospray ionization ESI Normal-phase silica gel chromatography FCC Grams g Hours h or hr (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo HATU [4,5-b]pyridinium 3-oxid hexafluorophosphate) Hepatitis B Virus HBV Acetic acid HOAc 1-Hydroxy-7-azabenzotriazole HOAt Hydroxybenzotriazole HOBt High-pressure liquid chromatography HPLC Hertz Hz Isopropyl alcohol iPrOH, IPA Potassium tert-butoxide KOtBu Lithium aluminum hydride LAH Liquid chromatography and mass spectrometry LCMS Lithium diisopropylamide LDA Lithium bis(trimethylsilyl)amide LHMDS Molar M multiplet m Mass to charge ratio m/z meta-Chloroperoxybenzoic acid mCPBA Methyl Iodide MeI Methanol MeOH Milligrams mg Megahertz MHz Minute min Milliliter mL Microliter μL Millimole mmol Micromole μmol Mass spectrometry MS Mesityl chloride MsCl Normal N Sodium acetate NaOAc Sodium tert-butoxide NaOt-Bu N-Methylmorpholine N-oxide NMO Nuclear magnetic resonance NMR CF₃SO₃— or triflate OTf Polymerase chain reaction PCR Petroleum ether PE Palladium (II) acetate Pd(OAc)₂ Palladium(II)bis(triphenylphosphine) dichloride Pd(PPh₃)₂Cl₂ Tetrakis(triphenylphosphine)palladium(0) Pd(PPh₃)₄ [1,1′-Bis(di-tert-butylphosphino)ferrocene] PdCl₂(dtbpf) or dichloropalladium(II) Pd(dtbpf)₂Cl₂ [1,1′-Bis(diphenylphosphino)ferrocene] PdCl₂(dppf) or dichloropalladium(II) Pd(dppf)₂Cl₂ 9-(2-Phosphonyl-methoxypropyly)adenine PMPA Parts per million ppm Precipitate ppt Polytetrafluoroethylene PTFE Pyridine Py Benzotriazol-1-yl-oxytripyrrolidinophosphonium PyBOP hexafluorophosphate Retention time R_(t) Ribonucleic Acid RNA Room temperature rt singlet s Saturated sat 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] Selectfluor ® octane bis (tetrafluoroborate) [2-(Trimethylsilyl)ethoxy]methyl acetal SEM Supercritical Fluid Chromatography SFC Temperature T triplet t Propylphosphonic anhydride T₃P Tert-Butyl alcohol tBuOH, t-BuOH Tetra-n-butylammonium fluoride TBAF Tetra-n-butylammonium iodide TBAI Tert-butyldiphenylsilyl chloride TBDPSCl Triethylamine TEA Trifluoroacetic acid TFA Tetrahydrofuran THF Thin layer chromatography TLC Toll-like receptor TLR Tumor necrosis factor TNF Tetrapropylammonium perruthenate TPAP Volume in milliliters of solvent per gram of substrate V, or volumes (Diethylamino)difluorosulfonium tetrafluoroborate XtalFluor ®

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now be described by reference to the illustrative synthetic schemes for their general preparation below and the specific examples to follow.

According to SCHEME 1, a commercially available or synthetically accessible compound of formula (Xa), where R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, and PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is alkylated with an alkylating agent such as methyl 2-bromo-2-methylpropanoate, and the like, to provide a compound of formula (XIa), where R^(b) is C₁₋₆alkyl optionally substituted with CO₂Me. A compound of formula (Xb), where PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is alkylated under conditions known to one skilled in the art, for example, reaction with or without a base such as NaH, Cs₂CO₃, K₂CO₃, and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as deuterium methyl iodide, allyl bromide, and the like, to provide a compound of formula (XIb), where R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl.

Deprotection of the nitrogen protecting group, employing conditions known to one skilled in the art provides a compound of formula (XIIa) and (XIIb). For example, the BOC protecting group is removed with acid such as TFA, HCl, and the like, in a suitable solvent such as DCM, and the like.

According to SCHEME 2, a commercially available or synthetically accessible compound of Formula (XIII), where R³ is H or C₁₋₆alkyl, is coupled with a compound of Formula (XIIb), where R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, under amide bond coupling conditions to provide a compound of Formula (XIV). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XII), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HO AT, propylphosphonic anhydride (T₃P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XIV).

A compound of Formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, is reacted with oxetane bromide, with a base such as cesium carbonate, with a phase transfer catalyst such as TBAI, in a solvent such as DMF, at a temperature of about 60-80° C. for a period of 5-6 h provides a compound of Formula (XVa) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl.

A compound of Formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, is reacted with 1-methyl-dibromoethane, with a base such as potassium carbonate, solvent such as DMF, at a temperature of about 20° C. provides a compound of Formula (XVb) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl.

A compound of Formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, is reacted with ethyl 2-bromopropanoate, with a base such as cesium carbonate, with a phase transfer catalyst such as TBAI, in a solvent such as DMF, at a temperature of about 40-60° C. for a period of 14-18 h provides a compound of Formula (XVc) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl.

A compound of Formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, is reacted with 1-methyl-dibromoethane, with a base such as cesium carbonate, with a phase transfer catalyst such as TBAI, solvent such as DMF, at a temperature of about 20° C. provides a compound of Formula (XVd) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl.

A commercially available or synthetically accessible compound of Formula (XIII), where R³ is H or C₁₋₆alkyl, is coupled with a compound of Formula (XIIa), where R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, and R^(b) is C₁₋₆alkyl optionally substituted with CO₂Me, under amide bond coupling conditions to provide a compound of Formula (XIVa). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XIaI), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HO AT, propylphosphonic anhydride (T₃P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XIVa).

A compound of Formula (XIV), where R³ is H or C₁₋₆alkyl, R^(a) is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, and R^(b) is C₁₋₆alkyl optionally substituted with CO₂Me is reacted with a trialkyl phosphate such as tributyl phosphate, a coupling reagent such as DIAD, solvent such as THF, at a temperature of about reflux provides a compound of Formula (XVe) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl.

According to SCHEME 3, a compound of Formula (XVI) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, can be prepared in two steps. For example, a compound of Formula (XVa) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 minutes to provide a compound of Formula (XVI) where the Boc group has been removed. The resulting product can then be reacted with an optionally substituted N-aryl phenyl carbamate such as phenyl (3-chloro-4-fluorophenyl)carbamate and a base such as TEA in a solvent such as DCM to provide a compound of Formula (XVI) where Ar is an optionally substituted aryl ring.

According to SCHEME 4, a compound of Formula (XVI) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl is reacted with a fluorinating reagent such as DAST, in a solvent such as DCM to provide a compound of Formula (XVII) where R² is CH₂F.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂SC₁-C₆alkyl, and m is 1 was prepared in two steps. First, a compound of Formula (XVI) was coupled with a sulfonating reagent such as MsCl, in presence of a base such as TEA, in a solvent such as DCM, at a temperature of about 25° C. for about 2 h to provide a compound of Formula (XVII) where R² is CH₂OMS and m is 1. Second, adding a sulfide nucleophile such as sodium methyl sulfide, in a solvent such as DMF, at a temperature of about 15° C. for about 16 h to provide a compound of Formula (XVII) where R² is CH₂SC₁-C₆alkyl, and m is 1.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂SC₁-C₆alkyl, and m is 1 is reacted with an oxidant such as m-CPBA, in a solvent such as DCM, at a temperature of about 30° C. for about 16 h to provide a compound of Formula (XVII) where R² is CH₂S(O)C₁-C₆alkyl or CH₂SO₂C₁-C₆alkyl and m is 1.

A compound of Formula (XVI) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl is reacted with NaOCN, with an acid such as TFA, in a solvent such as DCM, at a temperature of about 25° C. for about 32 h to provide a compound of Formula (XVII) where R² is CH₂O(O)NH₂.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is COOH, and m is 1 is reacted with an N(C₁₋₆alkyl)₀₋₂ such as methyl amine or dimethyl amine, using a coupling agent such as HATU, with a base such as DIPEA, in a solvent such as DMF to provide a compound of Formula (XVII) where R² is C(O) N(C₁₋₆alkyl)₀₋₂ and m is 1.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is C₃₋₆lactam, and m is 1 is prepared in 2 steps. First, a compound of Formula (XVII) where R² is CH₂NH₂ is reacted with haloalkyl acid chloride such as ClCH₂CH₂CH₂C(O)Cl, with a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XVII) where R² is CH₂NHC(O)CH₂CH₂CH₂Cl and m is 1. Second, reacting with a strong base such as NaH, in a solvent such as THF to provide a compound of Formula (XVII) R² is C₃₋₆lactam, and m is 1.

A compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂N₃, and m is 1 is reacted with with a phosphine such as triphenyl phosphine, in a solvent such a THF, water, or a mixture of both to provide a compound of Formula (XVII) where R² is CH₂NH₂.

According to SCHEME 5, a compound of Formula (XIX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂ N(C₁₋₆alkyl)₀₋₂ or C(O) N(C₁₋₆alkyl)₀₋₂, and m is 1 is prepared in two steps. First, a compound of Formula (XVIII) is reacted with a sulfonating reagent such as MsCl, with a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XIX) where R² is CH₂OH. Second, reacting with an amine such as N(C₁₋₆alkyl)₀₋₂, with a base such as potassium carbonate, in a solvent such as DMF, at a temperature of about 80° C. for about 24 h to provide a compound of (XIX) where R² is CH2 N(C₁₋₆alkyl)₀₋₂ or C(O) N(C₁₋₆alkyl)₀₋₂, and m is 1.

A compound of Formula (XVIII) where R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl is reacted with a C₁₋₆alkyl halide, C₁₋₆alkenyl halide, C₁₋₆haloalkyl triflate or halo-C₁₋₆alkyl-C₁₋₆cycloalkyl such as Mel, EtI, n-propyliodide, allylbromide, CHF₂CH₂OTf, CF₃CH₂OTf or c-PrCH₂Br with a strong base such as NaH, in a solvent such as DMF to provide a compound of Formula (XIX) where R² is CH₂OC₁₋₆alkyl, CH₂OC₁₋₆alkenyl, CH₂OC₁₋₆haloalkyl, or CH₂OC₁₋₆alkyl-C₁₋₆cycloalkyl.

A compound of Formula (XIX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is COOC₁₋₆alkyl, and m is 1 is prepared in 2 steps. First, a compound of Formula (XVIII) is reacted with an oxidant such as TPAP, a co-oxidant such as NMO, in a solvent such as MeCN to provide a compound of Formula (XIX) where R² is COOH. Second, reacting with a C₁₋₆alkyl-halide such as Mel with a base such as potassium carbonate, in a solvent such as MeCN to provide a compound of (XIX) where R² is COOC₁₋₆alkyl, and m is 1.

A compound of Formula (XVIII) where R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl is reacted with a silane such as TMSCF₃, a triflate salt such as silver triflate, a base such as 2-fluoropyridine, a desilation reagent such as potassium fluoride, a fluorinating reagent sue has Selectfluor®, in a solvent such as Ethyl Acetate to provide a compound of Formula (XIX) where R² is CH₂OCF₃ and m is 1.

A compound of Formula (XIX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂OMs, and m is 1 is reacted with an amine such as N(C₁₋₆alkyl)₀₋₂ or N(C₁₋₆haloalkyl)₀₋₂, a base such as potassium carbonate, in a solvent such as MeCN, at a temperature of about 80° C. for about 16 h to provide a compound of Formula (XIX) where R² is CH₂N(C₁₋₆alkyl)₀₋₂ or N(C₁₋₆haloalkyl)₀₋₂ and m is 1.

A compound of Formula (XIX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is COOH, and m is 1 is reacted with an amine such as N(C₁₋₆alkyl)₀₋₂, N(C₁₋₆haloalkyl)₀₋₂, or N(C₁₋₆alkyl)(C₁₋₆haloalkyl), a base such as 3-picoline, a sulfonating reagent such as MsCl, in a solvent such as MeCN, at a temperature of about 0° C. to 30° C. for about 1 h to provide a compound of Formula (XIX) where R² is C(O)N(C₁₋₆alkyl)₀₋₂, C(O)N(C₁₋₆haloalkyl)₀₋₂, or C(O)N(C₁₋₆alkyl)(C₁₋₆haloalkyl) and m is 1.

A compound of Formula (XIX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂NHC(O)C₁₋₆alkyl, and m is 1 is prepared in three steps. First, a compound of Formula (XIX) where R² is CH₂OMs and m is 1 is reacted with a nucleophilic azide such as sodium azide, in a solvent such as DMF, at a temperature of about 70° C. for about 16 h to provide a compound of Formula (XIX) where R² is CH₂N₃. Second, reacting with a phosphine such as triphenyl phosphine, in a solvent such a THF, water, or a mixture of both to provide a compound of Formula (XIX) where R² is CH₂NH₂. Third, reacting with a C₁₋₆alkyl anhydride such as acetic anhydride, a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XIX) where R² is CH₂NHC(O)C₁₋₆alkyl.

A compound of Formula (XIX) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is CH₂NH₂, and m is 1 is reacted with a C₁₋₆alkyl-SO₂-halide such as MsCl, a base such as TEA, in a solvent such as DCM to provide a compound of Formula (XIX) where R² is CH₂NH(SO₂C₁₋₆alkyl), and m is 1.

Method A:

According to SCHEME 6, a compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is as described in any of the examples above, and m is 1 is prepared in 2 steps. First, a compound of Formula (XIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XIX) where the Boc has been removed. Second, adding a reagent useful for forming an isocyanate such as triphosgene, an optionally substituted aryl amine such as analine, a base such as TEA, in a solvent such as DCM, at a temperature of about 25° C. for about 15 min to provide a compound of Formula (XVII) where Ar is an optionally substituted aryl ring.

Method B:

a compound of Formula (XVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is as described in any of the examples above, and m is 1 is prepared in 2 steps. First, a compound of Formula (XIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XIX) where the Boc has been removed. Second, adding an optionally substituted N-aryl phenyl carbamate such as phenyl (3-chloro-4-fluorophenyl)carbamate, as base such as TEA, in a solvent such as DCM to provide a compound of Formula (XVII) where Ar is an optionally substituted aryl ring.

According to SCHEME 7, a commercially available or synthetically accessible compound of formula (XXa), where R^(a) is C₁₋₆alkyl, and PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is protected with an a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, to provide a compound of formula (XXIa), where PG₂ is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like.

A compound of formula (XXIIa), where R^(a) is C₁₋₆alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, PG₂ is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R^(b) is CH₂CH₂OH is prepared in two steps from (XXIa). First, (XXIa) is alkylated under conditions known to one skilled in the art, for example, reaction with or without a base such as NaH, Cs₂CO₃, K₂CO₃, and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as 1-bromo-methyl acetate, and the like, to provide a compound of formula (XXIIa) where R^(b) is CH₂(O)OMe. Second, reduction under conditions known to one skilled in the art, for example, reduction using lithium borohydride, and the like, in a suitable solvent such as THF, and the like to provide a compound of formula (XXIIa), where R^(a) is C₁₋₆alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, PG₂ is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R^(b) is CH₂CH₂OH.

A commercially available or synthetically accessible compound of formula (XXb), where R^(a) is C₁₋₆alkyl, and PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, is alkylated under conditions known to one skilled in the art, for example, reaction with or without a base such as diisopropyl ethyl amine, NaH, Cs₂CO₃, K₂CO₃, and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as (2-bromoethoxy)(tert-butyl)dimethylsilane, and the like, to provide a compound of formula (XXIb), where R^(c) is CH₂CH₂OTBS, and the like.

A compound of formula (XXIIb), where R^(a) is C₁₋₆alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, R^(b) is Me or CH₂CH═CH₂, and R^(c) is a CH₂CH₂OH, and the like, is prepared in two steps. First, alkylating under conditions known to one skilled in the art, for example, reaction with or without a base such as diisopropyl ethyl amine, NaH, Cs₂CO₃, K₂CO₃, and the like, in a suitable solvent such as THF, DMF and the like, with an alkylating agent such as allyl bromide, methyl iodide, and the like, to provide a compound of formula (XXIIb) where R^(b) is Me or CH₂CH═CH₂. Second, deprotection under conditions known to one skilled in the art, for example, deprotection using hydrochloric acid, and the like, in a suitable solvent such as ethyl acetate, and the like to provide a compound of formula (XXIIb), where R^(a) is C₁₋₆alkyl, PG is a suitable nitrogen protecting group such as BOC, Bn, and the like, R^(c) is CH₂CH₂OH and R^(b) is Me or CH₂CH═CH₂.

Deprotection of the nitrogen protecting group, employing conditions known to one skilled in the art provides a compound of formula (XXIIIa) and (XXIIIb). For example, the BOC protecting group is removed with acid such as TFA, HCl, and the like, in a suitable solvent such as DCM, and the like.

Any of the above alkylation steps are optional. In absence of alkylation, a proton is understood to be in the place of R^(b) or R^(c).

According to SCHEME 8, a commercially available or synthetically accessible compound of Formula (XIII), where R³ is H or C₁₋₆alkyl, is coupled with a compound of Formula (XXIIIa), where R^(a) is C₁₋₆alkyl, PG₂ is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R^(b) is 2-ethanol, under amide bond coupling conditions to provide a compound of Formula (XXIVa). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XXIIIa), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HOAT, propylphosphonic anhydride (T₃P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XXIVa).

A commercially available or synthetically accessible compound of Formula (XIII), where R³ is H or C₁₋₆alkyl, is coupled with a compound of Formula (XXIIIb), where R^(a) is C₁₋₆alkyl, R^(c) is CH₂CH₂OH and R^(b) is Me or CH₂CH═CH₂, under amide bond coupling conditions to provide a compound of Formula (XXIVb). For example, an acid compound of Formula (XIII) is reacted with an amine of Formula (XXIIIb), in the presence of a dehydrating agent such as HOBt/EDAC, CDI, PyBOP, HATU, HOAT, propylphosphonic anhydride (T₃P), a suitably selected base such as DIPEA, TEA, and the like, in a solvent such as toluene, MeCN, EtOAc, DMF, THF, DCM, or a mixture thereof, to afford a compound of Formula (XXIVb).

A compound of Formula (XXIVa), where R³ is H or C₁₋₆alkyl, where R^(a) is C₁₋₆alkyl, PG₂ is a suitable nitrogen protecting group such as carboxybenzyl (Cbz), and the like, and R^(b) is 2-ethanol, is reacted with MsCl, with a base such as triethyl amine, in a solvent such as DCM, to provide a compound of Formula (XXVa) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, and R² is a suitable nitrogen protecting group such as carboxybenzyl (Cbz).

A compound of Formula (XXIVb), where R³ is H or C₁₋₆alkyl, where R^(a) is C₁₋₆alkyl, R^(c) is CH₂CH₂OH and R^(b) is Me or CH₂CH₂═CH₂, is reacted with MsCl, with a base such as triethyl amine, in a solvent such as DCM, to provide a compound of Formula (XXVa) where R³ is H or C₁₋₆alkyl and R¹ is C₁₋₆alkyl, and R² is Me or CH₂CH═CH₂.

Deprotection of the nitrogen protecting group, employing conditions known to one skilled in the art provides a compound of formula (XXVa) where R² is H. For example, the Cbz protecting group is removed with hydrogen and palladium over carbon, and the like, in a suitable solvent such as MeOH, and the like.

According to SCHEME 9, a compound of Formula (XXVI) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, is reacted with a reducing reagent such as hydrogen and palladium over carbon, in a solvent such as MeOH to provide a compound of Formula (XXVII) where R² is CH₂CH₂CH₃.

A compound of Formula (XXVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is CH₂CH₂OH, was prepared in two steps. First, a compound of Formula (XXVI) was oxidized with a reagent such as OsO₄, in presence of NaIO₄, in a solvent such as THF and water mixture, to provide a compound of Formula (XXVII) where R² is CH₂CH═O. Second, adding a reducing reagent such as sodium borohydride, in a solvent such as a THF and ethanol mixture, to provide a compound of Formula (XXVII) where R² is CH₂CH₂OH.

A compound of Formula (XXVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is CH₂CHF₂, was prepared in two steps. First, a compound of Formula (XXVI) was oxidized with a reagent such as OsO₄, in presence of NaIO₄, in a solvent such as THF and water mixture, to provide a compound of Formula (XXVII) where R² is CH₂CH═O. Second, adding a fluorinating agent such as DAST, in a solvent such as DCM, to provide a compound of Formula (XXVII) where R² is CH₂CHF₂.

According to SCHEME 9, a compound of Formula (XXVIII) where R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, is reacted under hydroboration conditions, using reagents such as BH₃-DMS, in a solvent such as THF, followed by a base such as sodium hydroxide, and an oxidant such as hydrogen peroxide to provide a compound of Formula (XXIX) where R² is CH₂CH₂CH₂OH. A compound of Formula (XXVIII) where R³ is H or C₁₋₆alkyl, and R¹ is C₁₋₆alkyl, is reacted under hydroboration conditions, using reagents such as BH₃-DMS, in a solvent such as THF, followed by a base such as sodium hydroxide, and an oxidant such as hydrogen peroxide to provide a compound of Formula (XXIX) where R² is CH₂CHOHCH₃.

Scheme 11

A compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is CH₂OH, was prepared in three steps. First, a compound of Formula (XXX) was coupled with a reagent such as 3-chloro-2-oxopropyl acetate, in presence of a suitable acid such as p-toluenesulfonic acid, in a solvent such as DCM. Second, adding a reagent such as MsCl, in presence of a suitable base such as pyridine, in a solvent such as DCM. Third, adding a suitable base such as sodium hydride, in a solvent such as THF, to provide a compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is CH₂OH.

A compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is Me, was prepared in three steps. First, a compound of Formula (XXX) was coupled with a reagent such as l-hydroxypropan-2-one, in presence of a suitable acid such as p-toluenesulfonic acid, in a solvent such as DCM. Second, adding a reagent such as MsCl, in presence of a suitable base such as pyridine, in a solvent such as DCM. Third, adding a suitable base such as sodium hydride, in a solvent such as THF, to provide a compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is Me.

A compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is CH(Et)OH, CH(Me)OH, or CH(cPr)OH was prepared in two steps. First, a compound of Formula (XXXII) was oxidized with a reagent such as DMP, in a solvent such as DCM. Second, adding a Grignard reagent such as EtMgBr, MeMgBr, or cPrMgBr, in a solvent such as THF to provide a compound of Formula (XXXI) where R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is CH(Et)OH, CH(Me)OH, or CH(cPr)OH.

Method A:

According to SCHEME 13, a compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, and R² is as described in any of the examples above is prepared in 2 steps. First, a compound of Formula (XXXI) or Formula (XXIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XXXI) or Formula (XXIX) where the Boc has been removed. Second, adding a reagent useful for forming an isocyanate such as triphosgene, an optionally substituted aryl amine such as analine, a base such as TEA, in a solvent such as DCM, at a temperature of about 25° C. for about 15 min to provide a compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring.

Method B:

A compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring, R³ is H or C₁₋₆alkyl, R¹ is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₁₋₆alkenyl, R² is as described in any of the examples above, and m is 1 is prepared in 2 steps. First, a compound of Formula (XXXI) or Formula (XXIX) is reacted with an acid such as TFA, in a solvent such as DCM, at a temperature of about 15° C. for about 30 min to provide a compound of Formula (XXXI) or Formula (XXIX) where the Boc has been removed. Second, adding an optionally substituted N-aryl phenyl carbamate such as phenyl (3-chloro-4-fluorophenyl)carbamate, as base such as TEA, in a solvent such as DCM to provide a compound of Formula (XXXIII) or Formula (XXVII) where Ar is an optionally substituted aryl ring.

Intermediate 1. tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-oxoacetyl)-4-oxo-piperidine-1-carboxylate

To LiHMDS (1 M, 652.44 mL, 1.30 eq) was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (100.00 g, 501.88 mmol, 1.00 eq) in THF (1.00 L) was added dropwise at −78° C. under N₂. The reaction mixture was stirred at −78° C. for 30 minutes under N₂. Diethyl oxalate (95.35 g, 652.44 mmol, 1.30 eq) was added dropwise. After addition, the reaction mixture was warmed to 15° C. over a period of 30 minutes and stirred at 15° C. for another 2 hours. TLC showed the reaction was completed. The reaction was quenched with aqueous saturated NH₄Cl (1.5 L) and then neutralized with dilute hydrochloric acid, the aqueous layer was extracted with EtOAc (800 mL*3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (165.00 g, crude) as a yellow oil and used directly for next step.

Step 2. Preparation of 5-tert-butyl-3-ethyl 1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate

A mixture of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate (165.00 g, 551.25 mmol, 1.00 eq) and NH₂NH₂.H₂O (35.71 g, 606.37 mmol, 1.10 eq) in AcOH (1.00 L) was degassed and purged with N₂ for 3 times. Then the mixture was stirred at 80° C. for 1 hour under N₂ atmosphere. TLC and LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL) and washed with Na₂CO₃ (1 N, 1.2 L). The aqueous phase was extracted with ethyl acetate (800 mL*2). The combined organic phase was washed with brine (1 L*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (130.00 g, 440.19 mmol, 79.85% yield) as a yellow solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.57-4.65 (m, 2H), 4.36 (d, J=7.03 Hz, 2H), 3.67-3.74 (m, 2H), 2.75 (t, J=5.65 Hz, 2H), 1.49 (s, 9H), 1.36-1.40 (m, 3H). LCMS: 296 [M+1]

Step 3. Preparation of tert-butyl 3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

Sodium metal (7.78 g, 338.60 mmol, 8.02 mL, 10.00 eq) was added to MeOH (100.00 mL) portionwise at 0° C., and the mixture was stirred at 15° C. for 0.5 hr under N₂. Then N-methylhydroxylamine (8.48 g, 101.58 mmol, 3.00 eq, HCl) was added to the mixture and the mixture was stirred at 15° C. for 0.5 hr under N₂. Then 5-tert-butyl 3-ethyl 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (10.00 g, 33.86 mmol, 1.00 eq) was added, the mixture was stirred at 70° C. for 16 hr under N₂ atmosphere. TLC showed the starting material was consumed completely and a new spot was detected mainly. The mixture was poured into ice-water (300 mL) and stirred at 5 min. Then the mixture was concentrated in vacuum to give the residue. The pH of the aqueous phase was adjusted to around 6 with diluted hydrochloride acid (1 N) and extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (300 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (8.00 g, 27.00 mmol, 79.73% yield) as a yellow solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.62 (brs, 2H) 3.70 (t, J=5.52 Hz, 2H) 3.31-3.58 (m, 3H) 2.74 (s, 2H) 1.48 (s, 9H). LCMS: 297 [M+1]

Step 4. Preparation of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of tert-butyl 3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydroPyrazolo [4,3-c]pyridine-5-carboxylate (8.00 g, 27.00 mmol, 1.00 eq), 3-bromooxetane (4.07 g, 29.70 mmol, 1.10 eq), TBAI (997.22 mg, 2.70 mmol, 0.10 eq) and Cs₂CO₃ (13.19 g, 40.50 mmol, 1.50 eq) in DMF (80.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 70° C. for 3 hr under N₂ atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (200 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (100 mL*3). The combined organic phase was washed with brine (300 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1/2) to give the title compound (4.50 g, 12.39 mmol, 45.88% yield, 97% purity) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.62 (brs, 2H) 4.53 (brs, 2H) 4.32-4.42 (m, 1H) 3.57-3.88 (m, 4H) 3.29 (br. s., 3H) 2.68-2.79 (m, 2H) 1.41-1.53 (m, 9H). LCMS: 353 [M+1].

The racemate of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (2.6 g) was separated by SFC to get both enantiomers E1 (1.2 g, the first peak one) and E2 (1.3 g, the second one) (SFC separation condition: Column: Chiralpak AD-3 100×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 3 mL/min Wavelength: 220 nm). Each of the enantiomers were separately used to prepare the urea targets with the two sequential Boc protection and urea formation steps.

Intermediate 2, 3-chloro-4-fluoro-N-methylaniline

Step 1. Preparation of tert-butyl N-(3-chloro-4-fluoro-phenyl)carbamate

To a mixture of 3-chloro-4-fluoro-aniline (1.00 g, 6.87 mmol, 1.00 eq) and (Boc)₂O (3.00 g, 13.74 mmol, 3.16 mL, 2.00 eq) in H₂O (10.00 mL) was added TEA (2.09 g, 20.61 mmol, 2.86 mL, 3.00 eq) dropwise at 15° C. under N₂. The mixture was stirred at 10-20° C. for 3 h. LCMS showed 3.6% starting material remained and 93.2% desired product was generated. The reaction mixture was extracted with DCM (10 mL*2). The combined organic phase was dried with hydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was rinsed with PE (2 mL). The solid was collected by filtration, and dried in high vacuo to give the title compound (1.10 g, 4.48 mmol, 65.21% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (br s, 1H), 7.60-7.81 (m, 1H), 7.23-7.44 (m, 2H), 3.33 (s, 2H), 2.37-2.60 (m, 11H), 1.47 (s, 9H).

Step 2. Preparation of tert-butyl N-(3-chloro-4-fluoro-phenyl)-N-methyl-carbamate

To a mixture of tert-butyl N-(3-chloro-4-fluoro-phenyl)carbamate (600.00 mg, 2.44 mmol, 1.00 eq) in DMF (5.00 mL) was added NaH (195.38 mg, 4.88 mmol, 60% purity, 2.00 eq) at 0-5° C. under N₂. The resulting mixture was stirred at 20° C. for 1 hr. Then CH₃I (1.04 g, 7.32 mmol, 455.70 μL, 3.00 eq) was added dropwise at 15-20° C. The resulting mixture was stirred for 2 hr. LCMS showed starting material consumed and 98.55% desired product formed. The mixture was poured into water (20 mL), and extracted with EtOAc (3*5 mL). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (500.00 mg, 1.93 mmol, 78.91% yield) as yellow oil, which was used directly in next step. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.30 (dd, J=2.01, 6.53 Hz, 1H), 7.26 (s, 1H), 7.04-7.14 (m, 2H), 3.22 (s, 3H), 1.39-1.52 (m, 9H)

Step 3. Preparation of 3-chloro-4-fluoro-N-methyl-aniline

To a solution of HCl in dioxane (4 M, 5.00 mL, 11.56 eq), was added tert-butyl N-(3-chloro-4-fluoro-phenyl)-N-methyl-carbamate (450.00 mg, 1.73 mmol, 1.00 eq) below 0° C. The resulted mixture was stirred at 0-5° C. for 1 h, then warmed naturally to 15-20° C. and stirred at 15-20° C. for 2 hr. LCMS showed the starting material was consumed and 98% desired product was formed. The resulting mixture was concentrated under reduced pressure to give the title compound (240.00 mg, 1.22 mmol, 70.76% yield, HCl) as white solid which was used directly in the next step without further purification.

Intermediate 3, tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl-5-(2-ethoxy-2-oxo-acetyl)-3,3-dimethyl-4-oxo-piperidine-1-carboxylate

To LiHMDS (1 M, 5.72 mL, 1.30 eq) was added a solution of tert-butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate (1.00 g, 4.40 mmol, 1.00 eq) in THF (10.00 mL) at −78° C. under N₂. The reaction mixture was stirred at −78° C. for 30 minutes. Diethyl oxalate (835.82 mg, 5.72 mmol, 781.14 μL 1.30 eq) was added dropwise. After addition, the reaction mixture was warmed to 15° C. and stirred for another 2 hours. TLC indicated starting material was consumed completely, and a major new spot with larger polarity was detected. The reaction was quenched with diluted HCl (1N, 40 mL) and then extracted with EtOAc (100 mL*3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (1.00 g, crude) as yellow oil. The product was used in the next step without purification.

Step 2. Preparation of 5-(tert-butyl) 3-ethyl 7,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

To a solution of tert-butyl 5-(2-ethoxy-2-oxo-acetyl)-3,3-dimethyl-4-oxo-piperidine-1-carboxylate (800.00 mg, 2.44 mmol, 1.00 eq) in EtOH (10.00 mL) was added NH₂NH₂H₂O (143.70 mg, 2.44 mmol, 139.51 μL 85% purity, 1.00 eq). The reaction mixture was stirred at 15° C. for 2 hours. TLC indicated the starting material was consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (80 mL*2), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (760.00 mg, 2.23 mmol, 91.50% yield, 95% purity) as yellow solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.61 (s, 2H) 4.33-4.38 (q, J=7.11 Hz, 2H) 3.44 (brs, 2H) 1.49 (s, 9H) 1.37-1.40 (t, J=7.09 Hz, 3H) 1.28 (s, 6H).

LCMS: 324 [M+1].

Step 3. Preparation of 5-tert-butoxycarbonyl-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid

To a solution of 5-(tert-butyl) 3-ethyl 7,7-dimethyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (900.00 mg, 2.78 mmol, 1.00 eq) in THF (10.00 mL) was added a solution of NaOH (222.64 mg, 5.57 mmol, 2.00 eq) in H₂O (2.00 mL), the reaction mixture was warmed to 50° C. and stirred at 50° C. for 5 hours. TLC showed the reaction was completed. The pH of the reaction mixture was adjusted to around 6 by adding diluted hydrochloride acid (2N, 10 mL), then extracted with EtOAc (100 mL*4) and water (20 mL), the organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (780.00 mg, 2.59 mmol, 93.10% yield, 98% purity) as white solid. The product was used in the next step directly without further purification. LCMS: 296 [M+1].

Step 4. Preparation of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of 5-tert-butoxycarbonyl-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c] pyridine-3-carboxylic acid (200.00 mg, 677.21 μmol, 1.00 eq) in THF (5.00 mL) was added T₃P (1.72 g, 2.71 mmol, 1.61 mL, 50% purity, 4.00 eq) and TEA (342.63 mg, 3.39 mmol, 469.36 μL 5.00 eq), followed by N-methylhydroxylamine (113.12 mg, 1.35 mmol, 2.00 eq, HCl), the reaction mixture was stirred at 40° C. for 16 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with EtOAc (80 mL) and washed with water (50 mL*2), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (70.00 mg, 215.80 μmol, 31.87% yield) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.64 (s, 2H) 3.39 (brs, 5H) 1.47 (s, 9H) 1.27 (s, 6H). LCMS: 269 [M+1-56].

Step 5. Preparation of tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,2,4,5,8,9-hexahydro pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(11H)-carboxylate

To a mixture of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7,7-dimethyl-4,6-dihydro-1H-pyrazolo[4,3-c]pyridine-5-carboxylate (70.00 mg, 215.80 μmol, 1.00 eq) and 3-bromooxetane (35.47 mg, 258.96 μmol, 1.20 eq) in DMF (2.00 mL) was added Cs₂CO₃ (105.47 mg, 323.70 μmol, 1.50 eq) and TBAI (7.97 mg, 21.58 μmol, 0.10 eq), the reaction mixture was warmed to 75° C. and stirred at 75° C. for 3 hours. LCMS showed 50% of the starting material was remained. The reaction mixture was stirred at 75° C. for another 3 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (50 mL*3), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (53.00 mg, crude) as yellow oil. The product was used in the next step directly without further purification.

LCMS: 381 [M+1].

Intermediate 4, tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate

To a solution of 1-benzyl-3-methyl-piperidin-4-one (2.00 g, 9.84 mmol, 1.00 eq) and Boc₂O (2.15 g, 9.84 mmol, 2.26 mL, 1.00 eq) in MeOH (50.00 mL) was added Pd/C (9.84 mmol, 1.00 eq) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (50 psi) at 20° C. for 16 hours. TLC (PE:EA=5:1) showed the reaction was completed. The mixture was filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA=0%˜15%) to afford the title compound (2.00 g, 9.38 mmol, 95.33% yield) as colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.16-4.24 (m, 1H), 3.22-3.33 (m, 1H), 2.86 (brs, 1H), 2.38-2.61 (m, 3H), 1.51 (s, 9H), 1.06 (d, J=6.7 Hz, 3H).

Step 2. Preparation of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-5-methyl-4-oxo-piperidine-1-carboxylate

To a solution of tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate (2.00 g, 9.38 mmol, 1.00 eq) in THF (40.00 mL) was added LiHMDS (1 M, 11.26 mL, 1.20 eq) dropwise at −60° C. The mixture was stirred at −60° C. for 30 min. Diethyl oxalate (1.51 g, 10.32 mmol, 1.41 mL, 1.10 eq) was added dropwise at −60° C. Then the mixture was stirred at 20° C. for 1 hr. TLC (PE:EA=5:1) showed the reaction was completed. The reaction was quenched by saturated NH₄Cl (20 mL) and extracted with EtOAc (60 mL*2). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum to afford the title compound (2.00 g, crude) as yellow oil.

Step 3. Preparation of 5-(tert-butyl) 3-ethyl 7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

To a solution of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-5-methyl-4-oxo-piperidine-1-carboxylate (2.00 g, 6.38 mmol, 1.00 eq) in EtOH (40.00 mL) was added NH₂NH₂.H₂O (394.59 mg, 6.70 mmol, 383.10 μL 85% purity, 1.05 eq). The mixture was stirred at 20° C. for 16 hr. Major desired product was detected via LCMS. The mixture was concentrated in vacuum. The residue was diluted with EtOAc (80 mL) and H₂O (30 mL). The organic phase was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA: 10%˜50%) to afford the title compound (1.00 g, 3.23 mmol, 50.61% yield) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=1.30-1.34 (m, 3H) 1.41 (t, J=7.09 Hz, 3H) 1.49-1.55 (m, 9H) 2.98-3.38 (m, 2H) 3.74-4.08 (m, 1H) 4.40 (q, J=6.78 Hz, 2H) 4.47-4.68 (m, 1H) 4.78 (d, J=17.19 Hz, 1H).

Step 4. Preparation of 5-tert-butoxycarbonyl-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid

To a solution of 5-(tert-butyl) 3-ethyl 7-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (1.00 g, 3.23 mmol, 1.00 eq) in THF (10.00 mL) was added a solution of NaOH (258.40 mg, 6.46 mmol, 2.00 eq) in H₂O (2.00 mL). The mixture was stirred at 40° C. for 16 hr. TLC (PE:EA=1:1) showed the reaction was completed and one major spot appeared. Adjusted the pH of the mixture to 5˜6 with 1N HCl (10 mL) and extracted with EtOAc (20 mL*2). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum to afford the title compound (850.00 mg, 2.95 mmol, 91.21% yield, 97.5% purity) as white solid. LCMS: 282 [M+1].

Step 5. Preparation of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of 5-tert-butoxy carbonyl-7-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-3-carboxylic acid (200.00 mg, 710.96 μmol, 1.00 eq) and N-methylhydroxylamine (237.52 mg, 2.84 mmol, 4.00 eq, HCl) in THF (5.00 mL) was added T₃P (1.81 g, 2.84 mmol, 1.69 mL, 50% purity, 3.99 eq) followed by TEA (575.54 mg, 5.69 mmol, 788.41 μL 8.00 eq). The mixture was heated to 40° C. for 16 hr. TLC (DCM:MeOH=10:1) showed two main spots appeared. The mixture was extracted with EtOAc (20 mL*2) and H₂O (20 mL). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated. The residue was purified by column chromatography (PE:EA=50%˜100%) to afford the title compound (66.00 mg, 212.66 μmol, 29.91% yield) as white solid. LCMS: 312 [M+1].

Step 6. Preparation of tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,2,4,5,8,9-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(11H)-carboxylate

To a solution of tert-butyl 3-[hydroxy(methyl)carbamoyl]-7-methyl-1,4,6,7-tetra hydropyrazolo[4,3-c]pyridine-5-carboxylate (60.00 mg, 193.33 μmol, 1.00 eq) in DMF (2.00 mL) was added Cs₂CO₃ (188.97 mg, 579.99 μmol, 3.00 eq) followed by 3-bromooxetane (31.78 mg, 232.00 μmol, 1.20 eq). The mixture was stirred at 75° C. for 4 hr. LCMS showed the reaction was completed, major desired product was detected. The mixture was diluted with EtOAc (60 mL) and H₂O (30 mL). Separated the organic layer and washed with H₂O (30 mL*3), dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum to afford the title compound (60.00 mg, crude) as yellow oil. LCMS: 367 [M+1].

Intermediate 5, tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-[ethyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (100.00 mg, 374.14 μmol, 1.00 eq) in DMF (3.00 mL) was added HATU (184.94 mg, 486.38 μmol, 1.30 eq), DIPEA (241.77 mg, 1.87 mmol, 326.72 μL 5.00 eq) and N-ethylhydroxylamine (109.48 mg, 1.12 mmol, 3.00 eq, HCl). The mixture was stirred at 80° C. for 16 hr. LCMS showed the desired product was detected and ˜20% starting material was remained. The mixture was poured into water (20 mL), and extracted with DCM (20 mL*2). The organic layer was washed with brine (30 mL*3), dried over anhydrous Na₂SO₄ and concentrated in vacuum. The crude was purified by Prep-TLC (Dichloromethane:Methanol=10:1) to give the title compound (36.00 mg, 115.65 μmol, 30.91% yield, 99.7% purity) as colorless oil. LCMS: 311[M+1].

Step 2. Preparation of tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl 3-[ethyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (36.00 mg, 116.00 μmol, 1.00 eq) and 3-bromooxetane (19.07 mg, 139.20 μmol, 1.20 eq) in DMF (2.00 mL) was added Cs₂CO₃ (45.35 mg, 139.20 μmol, 1.20 eq) and TBAI (4.28 mg, 11.60 μmol, 0.10 eq). The mixture was stirred at 75° C. for 3 hr. LCMS showed about 40% starting material 2 was remained. The mixture was stirred at 75° C. for another 3 hr. The mixture was diluted with ethyl acetate (40 mL), washed with brine (30 mL*3). The organic layer was dried over anhydrous Na₂SO₄, concentrated in vacuum. The crude was purified by prep-TLC (100% Ethyl acetate). The title compound (25.00 mg, 68.23 μmol, 58.82% yield) was obtained as the colorless oil.

Intermediate 6, tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

Step 1. Preparation of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate

To LiHMDS (1 M, 652.44 mL, 1.30 eq) was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (100.00 g, 501.88 mmol, 1.00 eq) in THF (1.00 L) dropwise at −78° C. under N₂. The reaction mixture was stirred at −78° C. for 30 minutes under N₂. Then diethyl oxalate (95.35 g, 652.44 mmol, 1.30 eq) was added dropwise. After addition, the reaction mixture was warmed to 15° C. over a period of 30 minutes and stirred at 15° C. for another 2 hours. TLC (PE/EA=3/1) showed the reaction was completed. The reaction was quenched with NH₄Cl (sat.aq, 1.5 L) and then neutralized with diluted hydrochloric acid, the aqueous layer was extracted with EtOAc (800 mL×3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (165.00 g, crude) as yellow oil and used directly for next step.

Step 2. Preparation of 5-tert-butyl 3-ethyl 1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate

A mixture of tert-butyl 3-(2-ethoxy-2-oxo-acetyl)-4-oxo-piperidine-1-carboxylate (165.00 g, crude, 551.25 mmol, 1.00 eq) and NH₂NH₂.H₂O (35.71 g, 606.37 mmol, 1.10 eq) in AcOH (1.00 L) was degassed and purged with N₂ for 3 times. Then the mixture was stirred at 80° C. for 1 hour under N₂ atmosphere. TLC (PE/EA=1/1) and LCMS showed the reaction was completed. The mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (800 mL) and washed with Na₂CO₃ (1 N, 1.2 L). The aqueous phase was extracted with ethyl acetate (800 mL×2). The combined organic phase was washed with brine (1 L×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (130.00 g, 440.19 mmol, 79.85% yield) as a yellow solid. LCMS: 296 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.57-4.65 (m, 2H), 4.36 (d, J=7.03 Hz, 2H), 3.67-3.74 (m, 2H), 2.75 (t, J=5.65 Hz, 2H), 1.49 (s, 9H), 1.36-1.40 (m, 3H).

Step 3. Preparation of 5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid

A mixture of 5-tert-butyl 3-ethyl 1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (10.00 g, 33.86 mmol, 1.00 eq) and NaOH (2.03 g, 50.79 mmol, 1.50 eq) in THF (100.00 mL) and H₂O (20.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 40° C. for 16 hr under N₂ atmosphere. Then the mixture was stirred at 50° C. for 4 hr, LCMS showed the reaction was completed. The mixture was diluted in water (100 mL) and extracted with EA (50 mL×2). The aqueous phase was separated and adjusted the pH6 by adding diluted hydrochloride acid (1 N), solid was precipitated out. The mixture was filtered and the cake was concentrated in vacuum to afford the title compound (8.00 g, 29.93 mmol, 88.40% yield, 100% purity) as a yellow solid. LCMS: 268 [M+1]

Step 4. Preparation of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

A mixture of 5-tert-butoxycarbonyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (3.00 g, 11.22 mmol, 1.00 eq), N-methylhydroxylamine (1.41 g, 16.83 mmol, 1.50 eq, HCl), T₃P (17.86 g, 56.10 mmol, 16.69 mL, 5.00 eq) and TEA (11.35 g, 112.20 mmol, 15.55 mL, 10.00 eq) in THF (30.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 50° C. for 16 hour under N₂ atmosphere. LCMS showed the reaction was completed. The mixture was poured into water (80 mL), the aqueous layer was adjusted pH4 by 1N HCl, then the aqueous layer was extracted with DCM (40 mL×3), the combined organic layer was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, PE/EA=100/1 to 1/1) to give the crude product which was rinsed with EtOAc to afford the title compound (1.30 g, 4.39 mmol, 39.10% yield, 100% purity) as a white solid. LCMS: 319 [M+23].

Intermediate 7, tert-butyl 2,5-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 6, 50.00 mg, 168.74 μmol, 1.00 eq) in DMF (2.00 mL) was added TBAI (6.23 mg, 16.87 μmol, 0.10 eq). The reaction mixture was stirred at 15° C. for 3 hr. LCMS showed 77% of the starting material remained and −8.5% of desired product was detected. The reaction mixture was stirred at 50° C. for another 24 hr. TLC indicated the starting material remained and two new spots formed. The reaction mixture was quenched by water (20 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with saturated NH₄Cl. The residue was purified by prep-TLC (PE/EA, 1/3) to give the title compound (10.00 mg, 29.73 μmol, 17.62% yield) was obtained as a white solid.

LCMS: 337 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) (pilot run EW4043-68) δ 4.60-4.76 (m, 3H), 4.48 (dd, J=5.52, 11.42 Hz, 1H), 3.88-4.04 (m, 1H), 3.73-3.85 (m, 1H), 3.66 (s, 1H), 3.31 (s, 3H), 2.79 (s, 2H), 1.62 (d, J=6.65 Hz, 3H), 1.49 (s, 9H).

Intermediate 8, tert-butyl 2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 3-[(2-ethoxy-1-methyl-2-oxo-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 6, 400.00 mg, 1.35 mmol, 1.00 eq) in THF (20.00 mL) was added t-BuOK (151.50 mg, 1.35 mmol, 1.00 eq) under N2. The reaction mixture was stirred at 0° C. for 1 hr. Then ethyl 2-bromopropanoate (232.00 mg, 1.28 mmol, 166.91 μL 0.95 eq) in THF (4.00 mL) was added dropwise under N₂. After addition, the reaction mixture was stirred at 15° C. for 2 hr. TLC (PE/EA, 1/2) indicated the starting material was consumed completely and two new spots formed. The reaction mixture was quenched by sat. aq. NH₄Cl (15 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with water (15 mL) and brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA, 2/1 to 1/1) to give the title compound (510.00 mg, 1.29 mmol, 95.29% yield) as a white solid.

Step 2. Preparation of tert-butyl 3-[(2-hydroxy-1-methyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetra hydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl 3-[(2-ethoxy-1-methyl-2-oxo-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (400.00 mg, 706.29 μmol, 1.00 eq) in THF (5.00 mL) was added NaBH₄ (26.72 mg, 706.29 μmol, 1.00 eq) followed by MeOH (200.00 μL at −10° C. The mixture was stirred at 10° C. for 2 hr. TLC showed the starting material was consumed and three spots appeared. The mixture was quenched by saturated NH₄Cl (10 mL) and extracted with EtOAc (20 mL*2). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (EA:MeOH=10:1) to get the title compound (80.00 mg, 225.73 μmol, 31.96% yield) as colorless oil.

Step 3. Preparation of tert-butyl 2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl 3-[(2-hydroxy-1-methyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (70.00 mg, 197.52 μmol, 1.00 eq) in THF (4.00 mL) was added tributylphosphane (79.92 mg, 395.04 μmol, 97.46 μL 2.00 eq) followed by DIAD (79.88 mg, 395.04 μmol, 76.81 μL 2.00 eq) under N₂. The mixture was heated to 60° C. for 16 hr. TLC showed the starting material consumed and one main spot appeared. The mixture was extracted with EtOAc (30 mL*2) and H₂O (20 mL). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (PE:EA=1:2) to get the title compound (42.00 mg, 124.86 μmol, 63.21% yield) as colorless oil.

Intermediate 9. tert-butyl 2,4,4-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate.

Step 1. Preparation of methyl-2-[tert-butoxycarbonyl(methyl)amino]oxy-2-methyl-propanoate

To a solution of CH₃ONa (587.78 mg, 10.88 mmol, 1.00 eq) in MeOH (20.00 mL) was added methyl 2-bromo-2-methyl-propanoate (1.97 g, 10.88 mmol, 1.41 mL, 1.00 eq) and tert-butyl N-hydroxy-N-methyl-carbamate (1.60 g, 10.88 mmol, 1.00 eq) at 15° C. The mixture was heated to 60° C. with stirring for 16 h. TLC (PE:EtOAc=5:1) showed that starting material was consumed completely and one main new spot formed. The mixture was evaporated to remove the solvent and get the residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 20/1) to obtain the title compound (2.30 g, 9.30 mmol, 85.49% yield) as off-white liquid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=3.74 (s, 3H), 3.11 (s, 3H), 1.48 (d, 4.9 Hz, 15H).

Step 2. Preparation of tert-butyl N-(2-hydroxy-1,1-dimethyl-ethoxy)-N-methyl-carbamate

LiBH₄ (704.60 mg, 32.35 mmol, 4.00 eq) was charged to a cooled three-necked round bottom flask at −78° C. under N₂, then a solution of methyl 2-[tert-butoxycarbonyl(methyl)amino]oxy-2-methyl-propanoate (2.00 g, 8.09 mmol, 1.00 eq) in THF (20.00 mL) was added dropwise. After addition, the reaction mixture was warmed to 0° C. and stirred at 0° C. for 2 hours. TLC (PE:EtOAc=2:1) showed that reactant 3 was consumed completely and one main spot formed. The mixture was quenched with 20 mL of water and filtered to get the filtrate. The filtrate was extracted with EtOAc (20 mL*3) and the organic phases were combined. The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated to get the residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 15/1) to obtain the title compound (1.30 g, 5.93 mmol, 73.32% yield) as off-white liquid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.60 (brs, 1H), 3.59 (br d, J=12.35 Hz, 1H), 3.01-3.21 (m, 4H), 1.49 (s, 9H), 1.15-1.33 (m, 6H).

Step 3. Preparation of 2-methyl-2-(methylaminooxy)propan-1-ol

To a solution of tert-butyl N-(2-hydroxy-1,1-dimethyl-ethoxy)-N-methyl-carbamate (1.30 g, 5.93 mmol, 1.00 eq) in dioxane (2.00 mL) was added HCl/dioxane (4 M, 6.00 mL, 4.05 eq) under stirring at 15° C. for 2 h. TLC (PE:EtOAc=3:1) showed that the starting material was consumed completely and one main spot formed. The mixture was directly evaporated to get the title compound (1.10 g, crude, HCl) as yellow oil. ¹H NMR (400 MHz, METHANOL-d₄) δ=3.75 (s, 2H), 2.95 (s, 3H), 1.37 (s, 6H).

Step 4. Preparation of tert-butyl 3-[(2-hydroxy-1,1-dimethyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (800.00 mg, 2.99 mmol, 1.00 eq) and 2-methyl-2-(methylaminooxy)propan-1-ol (604.89 mg, 3.89 mmol, 1.30 eq, HCl) in THF (8.00 mL) was added T₃P (3.81 g, 5.98 mmol, 3.56 mL, 50% purity, 2.00 eq) and TEA (2.42 g, 23.92 mmol, 3.32 mL, 8.00 eq). The mixture was stirred at 30° C. for 2 hr. LCMS showed 30% desired product and 40% byproduct with MS+1=747. The mixture was diluted with saturated NH₄Cl (50 mL) and extracted with EtOAc (50 mL*2). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (PE:EA:30%˜100%) to get the title compound (200.00 mg, 542.84 Mmol, 18.16% yield) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.70 (brs, 2H), 3.60-3.77 (m, 4H), 3.50 (brs, 3H), 2.77 (t, J=5.32 Hz, 2H), 1.49 (s, 9H), 1.36 (s, 6H).

Step 5. Preparation of tert-butyl 2,4,4-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl 3-[(2-hydroxy-1,1-dimethyl-ethoxy)-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 542.84 μmol, 1.00 eq) in THF (2.00 mL) was added tributylphosphane (219.66 mg, 1.09 mmol, 267.87 μL 2.00 eq) followed by DIAD (219.54 mg, 1.09 mmol, 211.09 μL 2.00 eq) under N₂. The mixture was heated to 80° C. for 16 hr. TLC (PE:EA=0:1) showed the starting material was consumed and one main spot appeared. The mixture was extracted with EtOAc (10 mL*2) and H₂O (10 mL). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-TLC (PE:EA=0:1) to give the title compound (150.00 mg, 428.07 μmol, 78.86% yield) as colorless oil.

Intermediate 10. tert-butyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of tert-butyl 3-(hydroxy(methyl)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 6, 100.00 mg, 337.47 μmol, 1.00 eq) and K₂CO₃ (93.28 mg, 674.94 μmol, 2.00 eq) in DMF (3.00 mL) was added 1,2-dibromoethane (69.74 mg, 371.22 μmol, 28.01 μL 1.10 eq) in one portion at 15° C. The mixture was stirred at 15° C. for 36 hours. LCMS and TLC (dichloromethane:methanol=10:1) showed the reaction was completed. The mixture was poured into water (15 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-TLC (dichloromethane:methanol=10:1) to afford the title compound (55.00 mg, 170.62 μmol, 50.56% yield, 100% purity) as a yellow solid. LCMS: 323 [M+1].

Intermediate 11. N-allylhydroxylamine

Step 1. Preparation of [ally(tert-butoxycarbonyl)amino]tert-butyl carbonate

To a solution of (tert-butoxycarbonylamino) tert-butyl carbonate (5.50 g, 23.58 mmol, 1.00 eq) in DMF (30.00 mL) was added K₂CO₃ (6.52 g, 47.16 mmol, 2.00 eq) and 3-bromoprop-1-ene (3.71 g, 30.65 mmol, 1.30 eq) under N₂, the reaction mixture was stirred at 50° C. for 12 hr. TLC indicated the starting material was consumed completely and one new spot formed. The reaction mixture was filtered and the filter cake was washed with EtOAc (100 mL×3), the organic layer was added water (200 mL) and extracted with EtOAc (200 mL %), the combined layers were washed with water (50 mL×3) and brine (150 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography to give the title compound (5.20 g, 19.03 mmol, 80.68% yield) as colorless oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=5.76-6.00 (m, 1H) 5.18-5.31 (m, 2H) 4.19 (d, J=5.77 Hz, 2H) 1.52 (s, 9H) 1.49 (s, 9H).

Step 2. Preparation of N-allylhydroxylamine

To a solution of [allyl(tert-butoxycarbonyl)amino]tert-butyl carbonate (1.90 g, 6.95 mmol, 1.00 eq) in DCM (35.00 mL) was added TFA (53.90 g, 472.74 mmol, 35.00 mL, 68.02 eq), the reaction mixture was stirred at 15° C. for 3 hr. TLC indicated the starting material was consumed completely and one new spot formed. The reaction mixture was concentrated in vacuum to give the title compound (1.31 g, crude, TFA) as a light yellow oil.

Intermediate 12, tert-butyl 2-allyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl3-[allyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of N-allylhydroxylamine (Intermediate 11, 1.05 g, 5.61 mmol, 1.50 eq, TFA) and TEA (3.07 g, 30.29 mmol, 4.20 mL, 8.10 eq) in THF (50.00 mL) was added T₃P (9.64 g, 15.15 mmol, 9.01 mL, 50% purity, 4.05 eq) and 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (1.00 g, 3.74 mmol, 1.00 eq), the reaction mixture was stirred at 30° C. for 40 min. LCMS showed the starting material was consumed completely and a peak (about 69%) with desired MS was detected. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (40 mL×3), the combined organic layers were washed with water (50 mL×3) and brine (50 mL), filtered, dried with anhydrous Na₂SO₄ and concentrated in vacuum to give the title compound (900.00 mg, 2.29 mmol, 61.21% yield, 82% purity) as a light yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=5.90 (s, 1H) 5.20-5.35 (m, 2H) 4.23-4.77 (m, 4H) 3.67 (s, 2H) 2.71 (s, 2H) 1.48 (s, 9H). LCMS: 323 [M+1].

Step 2. Preparation of tert-butyl 2-allyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate

To a mixture of tert-butyl 3-[allyl(hydroxy)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (80.00 mg, 248.17 μmol, 1.00 eq) and 1,2-dibromoethane (69.93 mg, 372.25 μmol, 28.08 μL 1.50 eq) in DMF (2.00 mL) was added Cs₂CO₃ (242.58 mg, 744.51 nmol, 3.00 eq) and TBAI (9.17 mg, 24.82 nmol, 0.10 eq), the reaction mixture was stirred at 30° C. for 16 hours. LCMS showed the starting material was consumed completely and about 60% of desired compound was detected. The reaction mixture was diluted with EtOAc (80 mL) and washed with water (50 mL*2), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (53.00 mg, 136.91 μmol, 55.17% yield, 90% purity) as yellow oil. LCMS: 349 [M+1].

Intermediate 13, 5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid

Step 1. Preparation of ethyl 3-aminobutanoate

SOCl₂ (28.84 g, 242.43 mmol, 17.59 mL, 2.50 eq) was added to EtOH (100.00 mL) dropwise at 0° C. under N₂. The mixture was stirred at 0° C. for 0.5 hr under N₂. Then 3-aminobutanoic acid (10.00 g, 96.97 mmol, 1.00 eq) was added to the mixture and the mixture was stirred at 25° C. for 1.5 hr under N₂. And then the mixture was stirred at 50° C. for 1 hr under N₂ atmosphere. TLC (DCM/MeOH=10/l) showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (16.00 g, 95.45 mmol, 98.43% yield, HCl) as black brown oil. ¹H NMR (400 MHz, METHANOL-d₄) δ=2.66 (d, J=7.15 Hz, 2H), 2.09-2.19 (m, 1H), 1.17 (d, J=6.53 Hz, 2H), −0.18 (d, J=6.65 Hz, 3H), −0.27 (s, 3H)

Step 2. Preparation of ethyl 3-[(3-ethoxy-3-oxo-propyl) amino]butanoate

To a solution of ethyl 3-aminobutanoate (10.00 g, 59.66 mmol, 11.24 mL, 1.00 eq, HCl) in EtOH (100.00 mL) was added NaOH (2.51 g, 62.64 mmol, 1.05 eq) followed by ethyl prop-2-enoate (7.17 g, 71.59 mmol, 7.79 mL, 1.20 eq). The mixture was heated to 80° C. and stirred at 80° C. for 16 hr. TLC (DCM:MeOH=10:1) showed the starting material remained and a new spot was appeared. The pH of the mixture was adjusted to 4 with HCl (1N) and extracted with EA (200 mL). The aqueous phase was adjust to pH8 with Na₂CO₃ (sat.aq) and then extracted with EA (200 mL×2). The combined organic layer was dried over Na₂SO₄, filtered and concentrated to afford the title compound (9.00 g, 38.91 mmol, 65.22% yield) as colorless oil.

Step 3. Preparation of ethyl 3-[tert-butoxycarbonyl-(3-ethoxy-3-oxo-propyl)amino]butanoate

To a mixture of ethyl 3-[(3-ethoxy-3-oxo-propyl)amino]butanoate (9.00 g, 38.91 mmol, 1.00 eq) and TEA (5.51 g, 54.47 mmol, 7.55 mL, 1.40 eq) in THF (50.00 mL) was added Boc₂O (8.49 g, 38.91 mmol, 8.94 mL, 1.00 eq) at 30° C. The mixture was stirred at 30° C. for 12 hours. TLC (PE/EA=5/1) and LCMS showed the reaction was completed. The mixture was poured into water (30 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1) to afford the title compound (7.00 g, 21.12 mmol, 54.29% yield) as yellow oil.

Step 4. Preparation of 1-tert-butyl 3-ethyl 6-methyl-4-oxo-piperidine-1,3-dicarboxylate

To a mixture of ethyl 3-[tert-butoxycarbonyl-(3-ethoxy-3-oxo-propyl)amino] butanoate (7.20 g, 21.73 mmol, 1.00 eq) in THF (200.00 mL) was added t-BuOK (2.68 g, 23.90 mmol, 1.10 eq) in one portion at −40° C. under N₂. The mixture was stirred at −40° C. for 1 hr. LCMS showed the reaction was completed. The mixture was poured into water (50 mL) and stirred for 3 min. The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with brine (50 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (5.00 g, 17.52 mmol, 80.64% yield) as yellow oil. LCMS: 186 [M-99].

Step 5. Preparation of tert-butyl 3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate

To a mixture of 1-tert-butyl 3-ethyl 6-methyl-4-oxo-piperidine-1,3-dicarboxylate (5.00 g, 17.52 mmol, 1.00 eq) in MeOH (30.00 mL) was added N₂H₄.H₂O (1.03 g, 17.52 mmol, 1.00 mL, 85% purity, 1.00 eq) in one portion at 30° C. under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (1.50 g, 5.92 mmol, 33.80% yield) as yellow solid. LCMS: 254 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 4.70-4.82 (m, 1H), 4.58-4.68 (m, 1H), 3.76-3.89 (m, 1H), 2.75-2.88 (m, 1H), 2.37-2.50 (m, 1H), 1.49 (s, 9H), 1.13 (d, 6.90 Hz, 3H)

Step 6. Preparation of tert-butyl 6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl 3-hydroxy-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (1.50 g, 5.92 mmol, 1.00 eq) in Py (5.00 mL) was added 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (3.17 g, 8.88 mmol, 1.50 eq) in one portion under N₂. The mixture was stirred at 20° C. for 12 hours. TLC (PE/EA=2/1) showed the reaction was completed. The mixture was concentrated in vacuum. The residue was diluted with ethyl acetate (150 mL) and poured into HCl (0.5 N, 20 mL) and stirred for 1 min. The aqueous phase was extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with brine (100 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1) to afford the title compound (1.40 g, 3.63 mmol, 61.37% yield) as yellow solid.

Step 7. Preparation of tert-butyl 6-methyl-3-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl 6-methyl-3-(trifluoromethylsulfonyloxy)-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 519.00 μmol, 1.00 eq) and [trifluoro(vinyl)-boranyl]potassium (1+) (208.56 mg, 1.56 mmol, 3.00 eq) in dioxane (2.00 mL) and H₂O (200.00 μL) were added XPHOS-Pd-G2 (Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)) (40.83 mg, 51.90 μmol, 0.10 eq) and K₃PO₄ (330.50 mg, 1.56 mmol, 3.00 eq) in one portion under N₂. The reaction vessel was sealed and heated under microwave at 140° C. for 2 hours. TLC (PE/EA=2/1) showed ˜10% of the starting material remained, 80% of the title compound was detected. The mixture was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1) to afford the title compound (190.00 mg, 656.59 μmol, 42.17% yield, 91% purity) as yellow oil. LCMS: 264 [M+1].

Step 8. Preparation of tert-butyl 3-formyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl 6-methyl-3-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (400.00 mg, 1.52 mmol, 1.00 eq) in THF (40.00 mL) and H₂O (8.00 mL) was added NaIO₄ (1.30 g, 6.08 mmol, 336.79 μL 4.00 eq) and OsO₄ (38.62 mg, 152.00 μmol, 7.88 μL 0.10 eq) in one portion at 20° C. The mixture was stirred at 20° C. for 3 hours. LCMS showed the reaction was completed. The mixture was quenched with Na₂SO₃ (sat.aq, 20 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (400.00 mg, crude) as yellow oil.

Step 9. Preparation of 5-tert-butoxycarbonyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid

To a mixture of tert-butyl 3-formyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-5-carboxylate (400.00 mg, crude, 1.51 mmol, 1.00 eq) in t-BuOH (20.00 mL) was added 2-methylbut-2-ene (1PD 0.56 g, 150.58 mmol, 16.00 mL, 99.72 eq) dropwise at 0° C., then a solution of NaH₂PO₄ (905.85 mg, 7.55 mmol, 5.00 eq) and sodium; chlorite (1.37 g, 15.10 mmol, 10.00 eq) in H₂O (10.00 mL) was added to the above mixture dropwise at 0° C. The mixture was stirred at 0° C. for 2 hours. LCMS showed the reaction was completed. The mixture was adjusted to pH9 with solid NaHCO₃, the aqueous phase was extracted with ethyl acetate (10 mL×2). The aqueous layer was acidified to pH4 with 2N HCl and extracted with ethyl acetate (10 mL×2). The combined organic phase was washed with brine (10 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to afford the title compound (320.00 mg, 910.03 μmol, 60.27% yield, 80% purity) as yellow solid. LCMS: 282 [M+1].

Intermediate 14, tert-butyl 4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of 5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 400.00 mg, 1.42 mmol, 1.00 eq) and N-(oxetan-3-yloxy) methanamine (585.72 mg, 5.68 mmol, 4.00 eq) in THF (5.00 mL) was added T₃P (2.71 g, 4.26 mmol, 2.53 mL, 50% purity, 3.00 eq) and TEA (7.29 g, 72.05 mmol, 9.99 mL, 50.74 eq) in one portion under N₂. The mixture was stirred at 50° C. for 12 hours. LCMS showed the reaction was completed and one peak was detected, whereas TLC (dichloromethane:methanol=10:1) showed three new points. The residue was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=100/1, 50/1), followed by prep-HPLC(base) to give the title compound (50.00 mg, 136.46 μmol, 9.61% yield) as a white solid. LCMS: 367 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 4.63-5.16 (m, 3H), 4.09-4.61 (m, 4H), 3.60-3.94 (m, 2H), 3.30 (s, 3H), 2.85-3.02 (m, 1H), 2.50-2.66 (m, 1H), 1.48 (s, 9H), 1.13 (dd, J=3.64, 6.78 Hz, 3H).

Intermediate 15, tert-butyl 6-methyl-3-(methyl(oxetan-3-yloxy)carbamoyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of 5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 400.00 mg, 1.42 mmol, 1.00 eq) and N-(oxetan-3-yloxy) methanamine (585.72 mg, 5.68 mmol, 4.00 eq) in THF (5.00 mL) was added T₃P (2.71 g, 4.26 mmol, 2.53 mL, 50% purity, 3.00 eq) and TEA (7.29 g, 72.05 mmol, 9.99 mL, 50.74 eq) in one portion under N₂. The mixture was stirred at 50° C. for 12 hours. LCMS showed the reaction was completed and one peak was detected, whereas TLC (dichloromethane:methanol=10:1) showed three new points. The residue was poured into water (30 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (30 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=100/1, 50/1), followed by prep-HPLC(base) to give the title compound (160.00 mg, 436.67 μmol, 30.75% yield) as white solid. LCMS: 367 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 5.11 (d, J=5.14 Hz, 2H), 4.86 (d, J=6.15 Hz, 3H), 4.75 (dd, J=5.02, 7.65 Hz, 2H), 4.08-4.26 (m, 1H), 3.48 (br. s., 3H), 2.91-3.05 (m, 1H), 2.52-2.65 (m, 1H), 1.49 (s, 9H), 1.13 (d, J=6.90 Hz, 3H).

Intermediate 16. 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate

Step 1. Preparation of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.00 g, 2.84 mmol, 1.00 eq) and NMO (2.50 g, 21.30 mmol, 2.25 mL, 7.50 eq) in MeCN (30.00 mL) was added TPAP (199.61 mg, 568.00 μmol, 0.20 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hr. LCMS showed the reaction was completed. The residue was concentrated in vacuum to afford the title compound (1.04 g, crude) as black brown solid. LCMS: 367 [M+1].

Step 2. Preparation of 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate

To a mixture of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (1.04 g, 2.84 mmol, 1.00 eq) and K2CO3 (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (5.00 mL) was added Mel (1.21 g, 8.52 mmol, 530.70 μL 3.00 eq) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. 12 hours. LCMS showed the reaction was not reacted. The starting material was recovered from the reaction mixture by extracted with ethyl acetate (20 mL*2) after neutralized with 1N HCl to pH 3. Then reacted again (To a mixture of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (1.04 g, 2.84 mmol, 1.00 eq) and K2CO3 (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (5.00 mL) was added Mel (1.21 g, 8.52 mmol, 530.70 μL 3.00 eq) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. for 12 hours). LCMS and TLC (ethyl acetate:petroleum ether=2:1) showed the reaction was completed. The residue was poured into water (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 mL*2). The combined organic phase was washed with brine (20 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/l, 2/1) to afford the title compound (150.00 mg, 394.33 μmol, 13.88% yield, 100% purity) as yellow oil. LCMS: 381 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 4.79-4.98 (m, 2H), 4.45-4.75 (m, 3H), 3.88 (s, 3H), 3.54-3.85 (m, 2H), 3.38 (s, 3H), 2.67-2.89 (m, 2H), 1.49 (s, 9H).

Intermediate 17, tert-butyl (R)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl(2R)-5-(2-ethoxy-2-oxo-acetyl)-2-methyl-4-oxo-piperidine-1-carboxylate

To a solution of tert-butyl (2R)-2-methyl-4-oxo-piperidine-1-carboxylate (4.00 g, 18.76 mmol, 1.00 eq) in THF (50.00 mL) was added LiHMDS (1 M, 22.51 mL, 1.20 eq) dropwise at −70° C. The mixture was stirred at −70° C. for 0.5 hr. Then diethyl oxalate (3.56 g, 24.38 mmol, 3.33 mL, 1.30 eq) was added dropwise at −70° C. The mixture was stirred at 10° C. for 1 hr. TLC (petroleum ether:ethyl acetate=5:1) showed the starting material consumed and one new spot appeared. The mixture was quenched by 1N HCl (500 mL) and extracted with ethyl acetate (300 mL*5). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum to get the title compound (5.00 g, crude) as yellow oil.

Step 2. Preparation of 5-tert-butyl 3-ethyl (6R)-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]Pyridine-3,5-dicarboxylate

To a solution of tert-butyl (2R)-5-(2-ethoxy-2-oxo-acetyl)-2-methyl-4-oxo-piperidine-1-carboxylate (5.00 g, 15.96 mmol, 1.00 eq) in EtOH (30.00 mL) was added NH₂NH₂.H₂O (939.75 mg, 15.96 mmol, 912.38 μL 85% purity, 1.00 eq). The mixture was stirred at 10° C. for 1 hr. TLC (petroleum ether (PE):ethyl acetate(EA)=1:1) showed the starting material consumed and one main spot appeared. The reaction mixture was concentrated in vacuum. The residue was purified by column chromatography (PE:EA: 20%˜60%) to get the title compound (3.60 g, 11.64 mmol, 72.91% yield) as a yellow solid.

Step 3. Preparation of (6R)-5-tert-butoxycarbonyl-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid

To a solution of 5-tert-butyl 3-ethyl (6R)-6-methyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate (3.60 g, 11.64 mmol, 1.00 eq) in THF (30.00 mL) was added a solution of NaOH (930.95 mg, 23.27 mmol, 2.00 eq) in H₂O (7.00 mL). The mixture was stirred at 50° C. for 16 hr. TLC (PE:EA=1:1) showed the starting material consumed and one main spot with higher polarity appeared. The pH of the mixture was adjusted to 5˜6 with 1N HCl. The mixture was diluted with ethyl acetate (300 mL) and H₂O (100 mL). The organic layer was separated, dried with Ns₂SO₄, and filtered. The filtrate was concentrated in vacuum to get the title compound (3.00 g, 10.66 mmol, 91.62% yield) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=4.93 (d, J=17.24 Hz, 1H), 4.68-4.75 (m, 1H), 4.04 (d, J=16.51 Hz, 1H), 2.82 (dd, J=6.05, 15.96 Hz, 1H), 2.52 (d, J=15.89 Hz, 1H), 1.39 (s, 9H), 1.02 (d, J=6.97 Hz, 3H).

Step 4. Preparation of tert-butyl(6R)-3-[hydroxy(methyl)carbamoyl]-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of (6R)-5-tert-butoxycarbonyl-6-methyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3-carboxylic acid (2.70 g, 9.60 mmol, 1.00 eq) and N-methylhydroxylamine (2.40 g, 28.79 mmol, 3.00 eq, HCl) in DMF (20.00 mL) was added HOBt (1.95 g, 14.40 mmol, 1.50 eq), PyBOP (7.49 g, 14.40 mmol, 1.50 eq) and DIEA (6.20 g, 47.99 mmol, 8.38 mL, 5.00 eq). The mixture was stirred at 30° C. for 3 hr. TLC (DCM:MeOH=10:1) showed the starting material was consumed and one main spot appeared. The mixture was extracted with ethyl acetate (150 mL*3) and H₂O (150 mL). The combined organic layer was washed with H₂O (150 mL*2), 1N HCl (80 mL) and saturated Na₂CO₃ (50 mL). The organic layer was dried with Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by colon chromatography (petroleum ether:ethyl acetate: 60%˜100%) to get the tile compound (2.00 g, 6.44 mmol, 67.13% yield) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=5.06 (d, J=13.82 Hz, 1H), 4.78-4.84 (m, 1H), 4.20 (brs, 1H), 3.40 (brs, 3H), 2.93 (dd, J=5.93, 15.71 Hz, 1H), 2.63 (d, J=15.89 Hz, 1H), 1.50 (s, 9H), 1.14 (d, J=6.85 Hz, 3H).

Step 5. Preparation of tert-butyl (R)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl (6R)-3-[hydroxy(methyl)carbamoyl]-6-methyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (2.00 g, 6.44 mmol, 1.00 eq) in DMF (20.00 mL) was added Cs₂CO₃ (6.30 g, 19.32 mmol, 3.00 eq) followed by 1,2-dibromoethane (1.81 g, 9.66 mmol, 728.81 μL 1.50 eq) and TBAI (238.03 mg, 644.00 μmol, 0.10 eq). The mixture was stirred at 50° C. for 16 hr. TLC (PE:EA=0:1) showed the starting material was consumed and one main spot appeared. The mixture was extracted with ethyl acetate (20 mL*2) and H₂O (20 mL). The combined organic layer was washed with H₂O (20 mL*2), dried with Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate=50%˜100%) to get the title compound (1.50 g, 4.19 mmol, 65.09% yield, 94% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.73-5.06 (m, 1H), 4.38-4.52 (m, 1H), 4.21-4.36 (m, 1H), 4.11 (d, J=17.48 Hz, 1H), 3.21 (s, 3H), 2.84-2.93 (m, 1H), 2.51 (d, J=15.77 Hz, 1H), 1.41 (s, 10H), 1.06 (d, J=6.97 Hz, 3H).

Intermediate 18, tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of (R)-5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (Intermediate 13, 2.30 g, 7.41 mmol, 1.00 eq) in DMF (20.00 mL) was added Cs₂CO₃ (7.24 g, 22.23 mmol, 3.00 eq) followed by 3-bromooxetane (1.32 g, 9.63 mmol, 1.30 eq) and TBAI (273.74 mg, 741.00 μmol, 0.10 eq). The mixture was stirred at 75° C. for 4 hr. LCMS showed 70% desired product. The mixture was extracted with ethyl acetate (20 mL*2) and H₂O (20 mL). The combined organic layer was washed with H₂O (20 mL*2), dried with Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether:ethyl acetate=50%˜100%) to get 1.8 g desired product with 85% purity. 1.5 g was re-purified by prep-HPLC (FA) to get 1.1 g of pure desired product, which was separated by SFC to afford both diastereomers (420 mg) and (470 mg). SFC separation condition: Instrument: SFC Thar_80_Q; Column: OD-10 μm; Mobile phase: A for CO₂ and B for Isopropanol (0.1% Ammonia); Isocratic: B 20%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

Intermediate 19. 2,2-difluoroethyl trifluoromethanesulfonate

To a solution of 2,2-difluoroethanol (500.00 mg, 6.09 mmol, 1.00 eq) and DIPEA (945.08 mg, 7.31 mmol, 1.28 mL, 1.20 eq) in DCM (5.00 mL) was added Tf₂O (1.89 g, 6.70 mmol, 1.11 mL, 1.10 eq) at 0° C. under N₂, and the mixture was stirred at 10° C. for 3 h. The starting material have lower boiling point and the reaction was not detected. The mixture was diluted with DCM (10 mL) and washed with water (20 mL*2) and brine (20 mL*1). The organic phase was dried over anhydrous Na₂SO₄ and filtered. DMF (1 mL) was added. The resulting mixture was concentrated in vacuo to get a DMF solution of (2,2,2-trifluoroethyl trifluoromethanesulfonate (5.68 mmol, 1 mL), which directly used in the next step.

Intermediate 20, 2,2,2-trifluoroethyl trifluoromethanesulfonate

To a solution of 2,2,2-trifluoroethanol (2.09 g, 20.84 mmol, 1.50 mL, 1.00 eq) and DIPEA (3.23 g, 25.01 mmol, 4.36 mL, 1.20 eq) in DCM (10.00 mL) was added Tf₂O (6.47 g, 22.92 mmol, 3.78 mL, 1.10 eq) at 0° C. under N₂, and the mixture was stirred at 10° C. for 3 h. The starting material have lower boiling point and the reaction was not detected. The mixture was diluted with DCM (10 mL) and washed with water (20 mL*2) and brine (20 mL*1). The organic phase was dried over anhydrous Na₂SO₄ and filtered. DMF (1.00 mL) was added. The resulting mixture was concentrated in vacuo to get a DMF solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (14.19 mmol, 1 mL) was obtained, directly used in the next step.

Intermediate 21. tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of [tert-butoxycarbonyl (trideuteriomethyl]aminol tert-butyl carbonate

A mixture of (tert-butoxycarbonylamino) tert-butyl carbonate (100.00 mg, 428.71 μmol, 1.00 eq), CD₃I (138.04 mg, 857.42 μmol, 2.00 eq) and K₂CO₃ (88.88 mg, 643.07 μmol, 1.50 eq) in DMF (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 50° C. for 16 hour under N₂ atmosphere. TLC showed the starting material was consumed completely and a new spot appeared. The mixture was poured into water (5 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (3 mL*3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (100.00 mg, 399.50 μmol, 93.19% yield) as a colorless oil, which was used directly for the next step.

Step 2. Preparation of N-(trideuteriomethyl)hydroxylamine

A mixture of [tert-butoxycarbonyl(trideuteriomethyl)amino] tert-butyl carbonate (100.00 mg, 399.50 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 67.62 eq). The mixture was stirred at 15° C. for 2 hour. TLC showed the starting material was consumed completely and a new spot appeared. The mixture was concentrated in vacuum to give (65.56 mg, 399.51 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for the next step.

Step 3. Preparation of tert-butyl 3-[hydroxy(trideuteriomethyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate

A mixture of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3-carboxylic acid (100.00 mg, 374.14 μmol, 1.00 eq), N-(trideuteriomethyl)hydroxylamine (61.40 mg, 374.14 μmol, 1.00 eq, TFA), T₃P (357.13 mg, 1.12 mmol, 333.77 μL 3.00 eq) and TEA (189.30 mg, 1.87 mmol, 259.32 μL 5.00 eq) in THF (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 15° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely and desired product was major. The mixture was poured into ice-water (5 mL) and stirred at 5 min. Then the mixture was concentrated in vacuum to give the residue. The pH of the aqueous phase was adjusted to around 6 by adding diluted hydrochloride acid (1 N) and extracted with ethyl acetate (3 mL*3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (75.00 mg, 238.02 μmol, 63.62% yield, 95% purity) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 4.62 (s, 2H) 3.71 (d, J=4.16 Hz, 2H) 2.70-2.78 (m, 2H) 1.48 (d, J=3.42 Hz, 9H). LCMS: 300 [M+1].

Step 4. Preparation of tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of tert-butyl 3-[hydroxy(trideuteriomethyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (75.00 mg, 250.55 μmol, 1.00 eq), 3-bromooxetane (41.18 mg, 300.66 μmol, 1.20 eq), TBAI (9.25 mg, 25.06 μmol, 0.10 eq) and Cs₂CO₃ (122.45 mg, 375.83 μmol, 1.50 eq) in DMF (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 70° C. for 3 hour under N₂ atmosphere. TLC showed the starting material was consumed completely and two new spots appeared. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-TLC (DCM/MeOH=10/1) to give the title compound (41.00 mg, 98.06 μmol, 39.14% yield, 85% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 4.47-4.72 (m, 4H) 4.31-4.43 (m, 1H) 3.59-3.95 (m, 4H) 2.77 (br. s., 2H) 1.49 (s, 9H). LCMS: 356 [M+1].

Intermediate 22, 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate

Step 1. Preparation of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (Intermediate 1, 1.00 g, 2.84 mmol, 1.00 eq) and NMO (2.50 g, 21.30 mmol, 2.25 mL, 7.50 eq) in MeCN (30.00 mL) was added TPAP (199.61 mg, 568.00 μmol, 0.20 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hr. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (1.04 g, crude) as black brown solid. LCMS: 367 [M+1].

Step 2. Preparation of 10-tert-butyl 4-methyl 2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxylate

To a mixture of 10-tert-butoxycarbonyl-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (1.04 g, crude, 2.84 mmol, 1.00 eq) and K₂CO₃ (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (20.00 mL) was added Mel (1.21 g, 8.52 mmol, 530.70 μL 3.00 eq) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. 12 hours. LCMS showed the reaction didn't react. The starting material was recovered: the reaction mixture was neutralized with HCl (1N, aq) to pH=3, then extracted with ethyl acetate (20 mL×2). The combined organic layer was dried over Na₂SO₄, filtered and concentrated to dryness. The reaction was performed again. To the recovered the starting material and K₂CO₃ (1.18 g, 8.52 mmol, 3.00 eq) in MeCN (20.00 mL) was added Mel (1.21 g, 8.52 mmol, 530.70 μL 3.00 eq) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. for 12 hours. LCMS and TLC (EA/PE=2/1) showed the reaction was completed, and 45% of the title compound was detected. The residue was poured into water (20 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (20 mL×2). The combined organic phase was washed with brine (20 mL×2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=10/1, 2/1) to afford the title compound (150.00 mg, 394.33 μmol, 13.88% yield, 100% purity) as yellow oil. LCMS: 381 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 4.79-4.98 (m, 2H), 4.45-4.75 (m, 3H), 3.88 (s, 3H), 3.54-3.85 (m, 2H), 3.38 (s, 3H), 2.67-2.89 (m, 2H), 1.49 (s, 9H).

Intermediate 23, tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 4-oxopyridine-1-carboxylate

To a solution of pyridin-4-ol (5.00 g, 52.58 mmol, 1.00 eq) in t-BuOH (250.00 mL) was added NaH (2.73 g, 68.35 mmol, 60% purity, 1.30 eq) under N₂, and the mixture was warmed to 50° C. in hot water bath until the mixture turned to a slurry. A solution of (Boc)₂O (14.92 g, 68.35 mmol, 15.71 mL, 1.30 eq) in t-BuOH (100.00 mL) was added dropwise, the mixture was stirred at 30° C. for 16 h. TLC indicated 50% of pyridin-4-ol was remained, and one major new spot with lower polarity was detected. The reaction mixture was quenched with water (200 mL), acidified to PH=7 with 10% HCl, and then extracted with ethyl acetate (300 mL*3), the combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography. The title compound (2.90 g, 14.86 mmol, 28.25% yield) was obtained as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.03-8.09 (m, 2H) 6.25-6.33 (m, 2H) 1.61 (s, 9H).

Step 2. Preparation of tert-butyl 4-oxo-2-vinyl-2,3-dihydropyridine-1-carboxylate

To a mixture of tert-butyl 4-oxopyridine-1-carboxylate (5.80 g, 29.71 mmol, 1.00 eq) and TMSCl (9.68 g, 89.13 mmol, 11.26 mL, 3.00 eq) in THF (50.00 mL) was added bromo(vinyl)magnesium (1 M, 44.57 mL, 1.50 eq) dropwise under N₂ at −78° C. The reaction mixture was warmed to 10° C. and stirred at 10° C. for 2 hours. TLC indicated the starting material consumed completely, and one major new spot with lower polarity was detected. The reaction was quenched with aqueous solution of NH₄Cl (120 mL) and then extracted with ethyl acetate (150 mL*3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (4.60 g, 20.19 mmol, 67.96% yield, 98% purity) as yellow oil. LCMS: 224 [M+1].

Step 3. Preparation of tert-butyl 4-oxo-2-vinyl-piperidine-1-carboxylate

To a solution of tert-butyl 4-oxo-2-vinyl-2,3-dihydropyridine-1-carboxylate (4.60 g, 20.60 mmol, 1.00 eq) in AcOH (30.00 mL) was added Zn (6.74 g, 103.00 mmol, 5.00 eq) under N₂, the reaction mixture was stirred at 70° C. for 4 hours. TLC indicated the starting material consumed completely, and two new spots with lower polarity were detected. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (200 mL) and washed with aqueous solution of NaHCO₃ (100 mL*3), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to afford the title compound (3.05 g, 13.40 mmol, 65.06% yield, 99% purity) as yellow oil. LCMS: 170 [M-56+1].

Step 4. Preparation of tert-butyl 5-(2-ethoxy-2-oxo-acetyl)-4-oxo-2-vinyl-piperidine-1-carboxylate

Cooled the three-necked round bottom flask to −78° C., LiHMDS (1 M, 11.54 mL, 1.30 eq) was added under N₂, then a solution of tert-butyl 4-oxo-2-vinyl-piperidine-1-carboxylate (2.00 g, 8.88 mmol, 1.00 eq) in THF (15.00 mL) was added dropwise, the reaction mixture was stirred at −78° C. for 30 minutes under N₂. Then a solution of diethyl oxalate (1.56 g, 10.66 mmol, 1.46 mL, 1.20 eq) in THF (10.00 mL) was added dropwise. After addition, the reaction mixture was stirred at −78° C. for 30 minutes, then at 10° C. for another 2 hours. TLC indicated tert-butyl 4-oxo-2-vinyl-piperidine-1-carboxylate consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was quenched with aqueous solution of NH₄Cl (100 mL) and then extracted with ethyl acetate (150 mL*2). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (2.00 g, crude) was obtained as yellow oil, which was used in the next step directly without further purification.

Step 5. Preparation of 5-tert-butyl 3-ethyl 6-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate

To a solution of tert-butyl 5-(2-ethoxy-2-oxo-acetyl)-4-oxo-2-vinyl-piperidine-1-carboxylate (2.00 g, 6.15 mmol, 1.00 eq) in EtOH (20.00 mL) was added a solution of NH₂NH₂H₂O (289.76 mg, 4.92 mmol, 281.32 μL 85% purity, 0.80 eq) in EtOH (2.00 mL) dropwise. The reaction mixture was stirred at 10° C. for one hour. LCMS showed one main peak with desired MS was detected. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with water (80 mL*2), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (1.30 g, 3.92 mmol, 63.74% yield, 97% purity) was obtained as yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=5.71 (ddd, J=17.32, 10.54, 4.89 Hz, 1H) 5.04-5.18 (m, 3H) 4.09-4.44 (m, 4H) 2.98-3.05 (m, 2H) 1.51 (s, 9H) 1.38 (t, J=7.09 Hz, 3H); LCMS: 322 [M+1].

Step 6. Preparation of 5-tert-butyl 3-ethyl 6-ethyl-1,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3,5-dicarboxylate

To a solution of 5-tert-butyl 3-ethyl 6-vinyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (1.50 g, 4.67 mmol, 1.00 eq) in MeOH (60.00 mL) was added Pd/C (200.00 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with H₂ three times, the mixture was stirred under H₂ (15 psi) at 10° C. for 16 hours. LCMS showed the starting material consumed completely and desired product was detected. The reaction mixture was filtered and the filtrate was concentrated to give the title compound (1.42 g, 4.22 mmol, 90.26% yield, 96% purity) as yellow solid, which was combined with another batch (187 mg) to separated by SFC to get a pair of enantiomers (E1: 0.76 g and E2: 0.77 g). SFC separation condition: Instrument: SFC Thar_80_Q; Column: IC-10 μm; Mobile phase: A for CO₂ and B for Methanol (0.1% Ammonia); Isocratic: B 25%; Flow rate: 55 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

E1: 1H NMR (400 MHz, CHLOROFORM-d) δ=4.92-5.25 (m, 1H) 4.47-4.76 (m, 1H) 4.32-4.45 (m, 2H) 3.95-4.18 (m, 1H) 2.95 (dd, J=16.02, 5.99 Hz, 1H) 2.74 (d, J=16.02 Hz, 1H) 1.43-1.54 (m, 11H) 1.39 (t, J=7.09 Hz, 3H) 0.90 (t, J=7.34 Hz, 3H). E2: 1H NMR (400 MHz, CHLOROFORM-d) δ=4.97-5.25 (m, 1H) 4.46-4.75 (m, 1H) 4.28-4.45 (m, 2H) 3.95-4.18 (m, 1H) 2.89-3.01 (m, 1H) 2.76 (d, J=16.02 Hz, 1H) 1.42-1.57 (m, 11H) 1.38 (t, J=7.09 Hz, 3H) 0.87-0.94 (m, 3H). Step 7. Preparation of 5-tert-butoxycarbonyl-6-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid

To a solution of 5-tert-butyl 3-ethyl 6-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (750.00 mg, 2.32 mmol, 1.00 eq) in MeOH (15.00 mL) was added a solution of NaOH (139.20 mg, 3.48 mmol, 1.50 eq) in H₂O (3.00 mL), the reaction mixture was stirred at 50° C. for 16 hours. LCMS showed one main peak with desired MS was detected. The pH of the reaction mixture was adjusted to around 6 by adding diluted HCl (1N, 15 mL). The resulting mixture was extracted with ethyl acetate (50 mL*3). The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (630.00 mg, crude) as white solid used in next step directly without further purification.

LCMS: 296 [M+1].

Step 8. Preparation of tert-butyl 6-ethyl-3-[hydroxy(methyl) carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of 5-tert-butoxycarbonyl-6-ethyl-1,4,6,7-tetrahydropyrazolo[4,3-c] pyridine-3-carboxylic acid (600.00 mg, 2.03 mmol, 1.00 eq) and N-methylhydroxylamine (339.09 mg, 4.06 mmol, 2.00 eq, HCl) in DMF (8.00 mL) was added PyBOP (1.27 g, 2.44 mmol, 1.20 eq), HOBt (329.15 mg, 2.44 mmol, 1.20 eq) and DIPEA (1.05 g, 8.12 mmol, 1.42 mL, 4.00 eq), the reaction mixture was stirred at 25° C. for 2 hours. LCMS showed about 40% of desired compound was detected. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL*3), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (560.00 mg, 1.55 mmol, 76.54% yield, 90% purity) as white solid. LCMS: 325 [M+1].

Step 9. Preparation of tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of tert-butyl 6-ethyl-3-[hydroxy(methyl)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (500.00 mg, 1.54 mmol, 1.00 eq) and 3-bromooxetane (253.14 mg, 1.85 mmol, 1.20 eq) in DMF (3.00 mL) was added Cs₂CO₃ (752.64 mg, 2.31 mmol, 1.50 eq) and TBAI (56.88 mg, 154.00 μmol, 0.10 eq), the reaction mixture was stirred at 55° C. for 4 hours. LCMS showed one main peak with desired MS was detected. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL*3). The organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (430.00 mg, 1.13 mmol, 73.39% yield) as white solid. LCMS: 381 [M+1].

Intermediate 24, (9R)-10-(tert-butoxycarbonyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid

Step 1. Preparation of (9R)-10-tert-butoxycarbonyl-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (Intermediate 18, 500.00 mg, 1.36 mmol, 1.00 eq, diastereomer separated by SFC) and NMO (1.19 g, 10.20 mmol, 1.08 mL, 7.50 eq) in MeCN (10.00 mL) was added TPAP (119.49 mg, 340.00 μmol, 0.25 eq). The mixture was stirred at 30° C. for 12 hr. LCMS showed the starting material was consumed completely, desired mass was major. The mixture was poured into water (20 mL) and washed with tert-butyl methyl ether (10 mL), the aqueous layer was acidified by 0.5 N HCl to pH3, extracted with DCM (20 mL×2), the organic layer was washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford the title compound (520.00 mg, crude) as a black brown solid.

LCMS: 381[M+1].

Intermediate 25, tert-butyl (9R)-2,9-dimethyl-4-(methylcarbamoyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of (9R)-10-(tert-butoxycarbonyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid (Intermediate 24, 256.00 mg, 672.99 μmol, 1.00 eq, diastereomer separated by SFC), methanamine (227.20 mg, 3.36 mmol, 5.00 eq, HCl), T₃P (856.53 mg, 1.35 mmol, 800.50 μL 50% purity, 2.00 eq), TEA (681.00 mg, 6.73 mmol, 932.88 μL 10.00 eq) in THF (10.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 70° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (20 mL) and extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (220.00 mg, 525.62 μmol, 78.10% yield, 94% purity) as a black blown solid. LCMS: 394[M+1].

Intermediate 26, 10-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 400.00 mg, 1.14 mmol, 1.00 eq) and NMO (1.00 g, 8.55 mmol, 902.37 μL 7.50 eq) in MeCN (20.00 mL) was added TPAP (100.16 mg, 285.00 μmol, 0.25 eq). The mixture was stirred at 20° C. for 12 h. The mixture was poured into water (40 mL) and washed with tert-butyl methyl ether (20 mL), the aqueous layer was acidified by 0.5 N HCl to pH=3, extracted with DCM (40 mL*2). The organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford the title compound (550.00 mg, crude) as brown oil.

LCMS: 367 [M+1].

Intermediate 27, tert-butyl 4-((2,2-difluoroethyl)(methyl)carbamoyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a mixture of 10-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid (Intermediate 26, 340.00 mg, 928.02 μmol, 1.00 eq), 3-PICOLINE (259.28 mg, 2.78 mmol, 270.08 μL 3.00 eq) and 2,2-difluoro-N-methyl-ethanamine (244.16 mg, 1.86 mmol, 2.00 eq, HCl) in MeCN (10.00 mL) was added MsCl (212.61 mg, 1.86 mmol, 143.66 μL 2.00 eq) at 0° C. The mixture was stirred at 25° C. for 1 h under N₂. The mixture was adjusted to pH=6 by 1N HCl, then diluted with H₂O (30 mL) and extracted Ethyl acetate (30 mL*2). The combined organic layers was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=l/l) to afford the title compound (290.00 mg, 634.36 μmol, 68.36% yield, 97% purity) as white solid.

LCMS: 444 [M+1].

Intermediate 28, tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq, single enantiomer separated by SFC), TEA (574.76 mg, 5.68 mmol, 787.34 μL 4.00 eq) in DCM (10.00 mL) was added MsCl (487.98 mg, 4.26 mmol, 329.72 μL 3.00 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 15° C. for 3 hour under N₂ atmosphere. TLC showed the starting material was consumed completely and new spot formed. The mixture was poured into ice-water (40 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (611.00 mg, crude) as a yellow solid. LCMS: 431[M+1]

Step 2. Preparation of tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of tert-butyl2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (611.00 mg, 1.42 mmol, 1.00 eq), NaN₃ (553.63 mg, 8.52 mmol, 6.00 eq) in DMF (10.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 70° C. for 16 hr under N₂ atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was diluted with ethyl acetate (10 mL) and washed with brine (30 mL,*3). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether/Ethyl acetate=100/l to 1:1) to give the title compound (500.00 mg, 1.26 mmol, 88.63% yield, 95% purity) as a colorless oil. LCMS: 378[M+1].

Intermediate 29, tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

Step 1. Preparation of tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 3.00 g, 8.19 mmol, 1.00 eq), TEA (4.14 g, 40.95 mmol, 5.67 mL, 5.00 eq) in DCM (40.00 mL) was added MsCl (3.75 g, 32.76 mmol, 2.53 mL, 4.00 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 3 hour under N₂ atmosphere. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was poured into ice-water (50 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (40 mL*2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 1:2) to give the title compound (3.40 g, 7.34 mmol, 89.66% yield, 96% purity) as a white solid. LCMS: 445 [M+1].

Step 2. Preparation of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of tert-butyl(9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.20 g, 2.70 mmol, 1.00 eq), NaN₃ (877.53 mg, 13.50 mmol, 5.00 eq) in DMF (20.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 70° C. for 16 hr under N₂ atmosphere. LCMS showed ˜10% starting material, ˜85% desired product. NaN₃ (351.01 mg, 5.40 mmol, 2.00 eq) was added to the mixture, the mixture was stirred at 70° C. for another 5 hr. LCMS showed the starting material was consumed completely, desired product was major. The mixture was diluted with ethyl acetate (60 mL) and washed with brine (100 mL,*3). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo to give the title compound (1.24 g, crude) as a yellow solid. LCMS: 392 [M+1]

Intermediate 30, tert-butyl (9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

A mixture of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 29, 1.06 g, 2.71 mmol, 1.00 eq), PPh₃ (1.42 g, 5.42 mmol, 2.00 eq) in THF (12.00 mL) and H₂O (2.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 0:1) to give the title compound (827.00 mg, 2.20 mmol, 81.00% yield, 97% purity) as a white solid.

LCMS: 366 [M+1]

Compound 001: N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide Step 1. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl 3-[methyl(oxetan-3-yloxy)carbamoyl]-1,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 1, 244.00 mg, 692.41 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (2.31 g, 20.26 mmol, 1.50 mL, 29.26 eq), and then the mixture was stirred at 30° C. for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (253.00 mg, 690.71 μmol, 99.75% yield, TFA) as yellow oil which was used directly for next step. LCMS: 253 [M+1].

Step 2. N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A mixture of N-methyl-N-(oxetan-3-yloxy)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c] pyridine-3-carboxamide (50.00 mg, 136.50 μmol, 1.00 eq, TFA), phenyl N-(3-bromophenyl)carbamate (39.88 mg, 136.50 μmol, 1.00 eq), TEA (20.72 mg, 204.75 μmol, 28.38 μL 1.50 eq) in DCM (2.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed desired mass was detected. The mixture was poured into water (5 mL) and stirred for 5 min. The aqueous phase was extracted with DCM (3 mL×3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to afford the title compound (25.00 mg, 54.96 μmol, 40.27% yield, 99% purity) as a white solid. LCMS: 450/452 [M+1]. ¹H NMR (400 MHz, MeOD) 7.68 (s, 1H), 7.33-7.35 (m, 1H), 7.15-7.17 (m, 2H), 4.86 (s, 2H), 4.53-4.73 (m, 2H), 4.35-4.37 (m, 1H), 3.82-3.84 (m, 2H), 3.71-3.73 (m, 1H), 3.66-3.67 (m, 1H), 3.32 (s, 3H), 2.81-2.84 (m, 2H).

Compounds 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 015, 016, 017, 018, 020, 021, 022, 023, 024, 025, 026, 027, 028, 029, 030, 031, 032, 033, 034, and 035 were prepared m a manner analogous to Compound 001.

Compound 002: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(m-tolyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 386.2

Compound 003: N-(2-chloro-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 424.1,

Compound 004: N-(3-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 468.1.

Compound 005: N-(3,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 408.1.

Compound 006: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3,4,5-trifluorophenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 426.1. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.24 (dd, J=10.29, 6.53 Hz, 2H) 4.71 (s, 2H) 4.48-4.62 (m, 2H) 4.32-4.41 (m, 1H) 3.82 (t, J=4.89 Hz, 2H) 3.70-3.77 (m, 1H) 3.62-3.68 (m, 1H) 3.31-3.33 (m, 3H) 2.82 (t, J=5.77 Hz, 2H).

Compound 007: N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 442.1.

Compound 008: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 440.1. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.82 (s, 1H) 7.66 (d, J=8.03 Hz, 1H) 7.46 (t, J=8.03 Hz, 1H) 7.31 (d, J=7.53 Hz, 1H) 4.77 (s, 2H) 4.51-4.64 (m, 2H) 4.33-4.43 (m, 1H) 3.82-3.93 (m, 2H) 3.63-3.81 (m, 2H) 3.33-3.36 (m, 3H) 2.86 (t, J=5.77 Hz, 2H).

Compound 009: N-(3-ethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 400.2. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.22 (s, 1H) 7.17 (m, 2H) 6.88 (m, 1H) 4.73 (s, 2H) 4.50-4.63 (m, 2H) 4.31-4.41 (m, 1H) 3.80-3.89 (m, 2H) 3.70-3.77 (m, 1H) 3.62-3.69 (m, 1H) 3.31-3.34 (m, 3H) 2.83 (t, J=5.65 Hz, 2H) 2.61 (q, J=7.53 Hz, 2H) 1.22 (t, J=7.65 Hz, 3H)

Compound 010: N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 486.0.

Compound 011: N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458.1.

Compound 011_E1: (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=2.8, 6.0 Hz, 1H), 7.56-7.64 (m, 1H), 7.15 (t, J=9.3 Hz, 1H), 6.63 (s, 1H), 4.74 (d, J=3.4 Hz, 2H), 4.54-4.65 (m, 2H), 4.39-4.48 (m, 1H), 3.84-3.96 (m, 3H), 3.72-3.83 (m, 1H), 3.35 (s, 3H), 2.89 (t, J=5.8 Hz, 2H), 1.92 (brs, 1H).

*Pure but unknown enantiomer.

Compound 011_E2: (R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.66 (dd, J=6.09, 2.70 Hz, 1H) 7.55-7.61 (m, 1H) 7.13 (t, J=9.41 Hz, 1H) 6.64 (s, 1H) 4.72 (s, 2H) 4.51-4.62 (m, 2H) 4.37-4.46 (m, 1H) 3.75-3.93 (m, 4H) 3.33 (s, 3H) 2.86 (t, J=5.71 Hz, 2H) 2.02 (br. s., 1H).

*Pure but unknown enantiomer.

Compound 012: N-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 440.0.

Compound 013: N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 442.1 ¹H NMR (400 MHz, METHANOL-d₄) δ=7.60 (t, J=7.91 Hz, 1H) 7.19 (t, J=9.66 Hz, 1H) 4.73 (s, 2H) 4.49-4.63 (m, 2H) 4.30-4.44 (m, 1H) 3.84 (s, 2H) 3.61-3.78 (m, 2H) 3.33-3.39 (m, 3H) 2.83 (t, J=5.65 Hz, 2H).

Compound 014: N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 486.0.

Compound 015: N-(3-bromo-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 486.0.

Compound 016: N-(2,5-dimethylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 400.2.

Compound 017: N-(5-bromo-2-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 464.1.

Compound 018: N-(5-bromo-4-fluoro-2-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 482.0. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.42 (d, J=6.78 Hz, 1H) 7.09 (d, J=9.54 Hz, 1H) 4.74 (s, 2H) 4.50-4.64 (m, 2H) 4.34-4.44 (m, 1H) 3.84 (t, J=5.14 Hz, 2H) 3.71-3.78 (m, 1H) 3.63-3.69 (m, 1H) 3.32 (m, 3H) 2.83 (t, J=5.52 Hz, 2H) 2.19 (s, 3H).

Compound 019: 4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.55 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 23.80 eq) and then the mixture was stirred at 15° C. for 30 min. TLC showed the starting material was consumed completely, and major desired product. The mixture was concentrated in vacuum to give the title compound (207.00 mg, 565.13 μmol, 99.57% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2: 4-(hydroxymethyl)-2-methyl-N-(3-methylcyclohexyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A mixture of 3-methylcyclohexanamine (30.00 mg, 235.79 μmol, 1.00 eq, HCl) and TEA (146.00 mg, 1.44 mmol, 200.00 μL 9.25 eq) in DCM (2.0 mL) was added triphosgene (46.27 mg, 155.92 μmol, 1.00 eq) at 0° C. The mixture was stirred at 25° C. for 12 min. Then 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (50.00 mg, 136.50 μmol, 0.5 eq, TFA) and TEA (100.00 μL 3.06 eq) was added to the reaction. The resulting mixture was stirred at 25° C. for 12 min. LCMS showed the reaction was completed. The solvent was evaporated in vacuo. The residue was adjusted to pH=6 and purified by prep-HPLC (FA) to afford the title compound. LCMS (M+1): 392.2.

Compound 020: 4-(hydroxymethyl)-N-(3-iodophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 498.0.

Compound 021: N-(3-(difluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 422. ¹H NMR (400 MHz, CHLOROFORM-d) δ=ppm 7.58-7.63 (m, 1H) 7.48 (s, 1H) 7.37 (t, J=7.84 Hz, 1H) 7.15-7.22 (m, 1H) 6.79 (s, 1H) 6.61 (s, 1H) 6.47 (s, 1H) 4.73 (s, 2H) 4.49-4.60 (m, 2H) 4.42 (s, 1H) 3.70-3.95 (m, 4H) 3.31 (s, 3H) 2.86 (s, 2H) 2.24-2.52 (m, 1H).

Compound 022: N-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 492. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.84 (dd, J=6.02, 2.64 Hz, 1H) 7.52 (dd, J=5.21, 2.57 Hz, 1H) 6.76 (s, 1H) 4.71 (d, J=3.89 Hz, 2H) 4.56 (d, J=13.30 Hz, 2H) 4.43 (s, 1H) 3.86 (dd, J=7.15, 5.52 Hz, 4H) 3.33 (s, 3H) 2.87 (t, J=5.71 Hz, 2H) 1.89-2.11 (m, 1H).

Compound 023: N-(2,3-dichloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 458/460. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.05 (dd, J=9.35, 5.21 Hz, 1H) 7.09 (t, J=8.78 Hz, 1H) 6.97 (s, 1H) 4.73-4.82 (m, 2H) 4.51-4.62 (m, 2H) 4.36-4.46 (m, 1H) 3.75-3.93 (m, 4H) 3.33 (s, 3H) 2.89 (t, J=5.71 Hz, 2H) 1.94 (brs, 1H).

Compound 024: N-(3,4-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 458. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.88-8.01 (m, 1H), 7.23 (dd, J=1.9, 9.1 Hz, 1H), 6.70 (d, J=3.1 Hz, 1H), 4.76 (s, 2H), 4.51-4.65 (m, 2H), 4.34-4.48 (m, 1H), 3.72-3.96 (m, 4H), 3.34 (s, 3H), 2.89 (t, J=5.7 Hz, 2H).

Compound 025: N-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS[M+1]: 474/476 ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (d, J=2.38 Hz, 1H) 7.60 (dd, J=8.72, 2.45 Hz, 1H) 7.41 (d, J=8.66 Hz, 1H) 6.74 (s, 1H) 4.72 (s, 2H) 4.51-4.61 (m, 2H) 4.37-4.47 (m, 1H) 3.77-3.93 (m, 4H) 3.32 (s, 3H) 2.86 (t, J=5.71 Hz, 2H) 2.04 (d, J=15.06 Hz, 1H).

Compound 026: N-(3-chloro-4-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS[M+1]: 420. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.51 (d, J=1.8 Hz, 1H), 7.12-7.20 (m, 2H), 6.48 (s, 1H), 4.72 (s, 2H), 4.51-4.64 (m, 2H), 4.35-4.47 (m, 1H), 3.74-3.97 (m, 4H), 3.34 (s, 3H), 2.87 (t, J=5.7 Hz, 2H), 2.33 (s, 3H), 1.98 (brs, 1H).

Compound 027: N-(4,5-dichloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 458/460. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.25-8.38 (m, 1H), 7.21 (d, J=10.54 Hz, 1H), 6.61-6.69 (m, 1H), 4.74 (s, 2H), 4.51-4.63 (m, 2H), 4.35-4.47 (m, 1H), 3.86 (d, J=16.06 Hz, 4H), 3.33 (s, 3H), 2.88 (t, J=5.77 Hz, 2H), 1.81-1.92 (m, 1H).

Compound 028: N-(3-chloro-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 442. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.30-7.40 (m, 1H) 7.19-7.24 (m, 1H) 6.39-6.74 (m, 1H) 4.69 (d, J=2.38 Hz, 2H) 4.50-4.62 (m, 2H) 4.36-4.48 (m, 1H) 3.72-3.95 (m, 4H) 3.33 (s, 3H) 2.86 (t, J=5.58 Hz, 2H) 1.81-1.99 (m, 1H).

Compound 028_E1: (S*)-N-(3-chloro-4,5-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 442. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.33 (ddd, J=2.8, 6.4, 12.0 Hz, 1H), 7.21 (td, J=2.4, 5.2 Hz, 1H), 6.74 (brs, 1H), 4.69 (s, 2H), 4.49-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.71-3.92 (m, 4H), 3.31 (s, 3H), 2.84 (t, J=5.6 Hz, 2H), 2.28 (s, 1H).

*Pure but unknown enantiomer.

Compound 029: 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3-(pentafluoro-16-sulfanyl)phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 498. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.86 (t, J=1.94 Hz, 1H) 7.60 (d, J=8.03 Hz, 1H) 7.34-7.45 (m, 2H) 6.80 (brs, 1H) 4.74 (s, 2H) 4.51-4.61 (m, 2H) 4.38-4.47 (m, 1H) 3.74-3.94 (m, 4H) 3.32 (s, 3H) 2.87 (t, J=5.77 Hz, 2H) 2.13 (brs, 1H).

Compound 030: N-(3-chlorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 406. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.51 (s, 1H), 7.16-7.25 (m, 2H), 7.01 (m, 1H), 6.69 (s, 1H), 4.70 (s, 2H), 4.49-4.60 (m, 2H), 4.36-4.45 (m, 1H), 3.70-3.93 (m, 4H), 3.31 (s, 3H), 2.85 (t, J=8.0 Hz, 2H), 2.40 (s, 1H).

Compound 031_E1: (S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 424. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.55 (dd, J=4.0, 8.0 Hz, 1H), 7.15-7.23 (m, 1H), 6.99-7.08 (m, 1H), 6.69 (s, 1H), 4.69 (s, 2H), 4.60-4.49 (m, 2H), 4.36-4.46 (m, 1H), 3.71-3.92 (m, 4H), 3.29-3.34 (m, 3H), 2.84 (t, J=8.0 Hz, 2H), 2.42 (s, 1H).

*Pure but unknown enantiomer.

Compound 031_E2: (R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 424. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.56-7.58 (dd, J=6.53, 2.64 Hz, 1H) 7.17-7.20 (dt, J=8.88, 3.40 Hz, 1H) 7.03-7.08 (m, 1H) 6.49 (s, 1H) 4.57-4.70 (s, 2H) 4.52-4.54 (m, 2H) 4.40-4.42 (m, 1H) 3.79-3.89 (m, 4H) 3.32 (s, 3H) 2.84-2.87 (t, J=5.77 Hz, 2H) 1.89-1.94 (m, 1H).

*Pure but unknown enantiomer.

Compound 032_E1: (S*)-N-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 468/470. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=4.0, 8.0 Hz, 1H), 7.22-7.26 (m, 1H), 7.03 (t, J=8.0 Hz, 1H), 6.69 (s, 1H), 4.69 (s, 2H), 4.49-4.61 (m, 2 H), 4.36-4.45 (m, 1H), 3.71-3.92 (m, 4H), 3.31 (s, 3H), 2.84 (t, J=8.0 Hz, 2H), 2.42 (s, 1H).

*Pure but unknown enantiomer.

Compound 033_E1: (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 469/471. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.10-8.18 (m, 1H), 8.06 (d, J=5.52 Hz, 1H), 6.99-7.10 (m, 1H), 4.76 (s, 2H), 4.50-4.62 (m, 2H), 4.37-4.46 (m, 1H), 3.71-3.95 (m, 4H), 3.32 (s, 3H), 2.89 (t, J=5.71 Hz, 2H), 2.20 (d, J=19.58 Hz, 1H).

*Pure but unknown enantiomer.

Compound 034_E1: (S*)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 415. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (dd, J=4.0, 8.0 Hz, 1H), 7.55-7.62 (m, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.73 (s, 1H), 4.71 (d, J=4.0 Hz, 2H), 4.51-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.74-3.94 (m, 4H), 3.33 (s, 3H), 2.86 (t, J=8.0 Hz, 2H), 2.02 (s, 1H).

*Pure but unknown enantiomer.

Compound 035_E1: (S*)-N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 404. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.22 (dd, J=4.0, 8.0 Hz, 1H), 7.05-7.12 (m, 1H), 6.91 (t, J=8.0 Hz, 1H), 6.57 (s, 1H), 4.69 (s, 2H), 4.48-4.59 (m, 2H), 4.35-4.43 (m, 1H), 3.68-3.92 (m, 4H), 3.29 (s, 3H), 2.83 (t, J=5.6 Hz, 2H), 2.66 (brs, 1H), 2.23 (d, J=1.6 Hz, 3H).

*Pure but unknown enantiomer.

Compound 038_E1: (S*)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4Hpyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031_E1, 20.00 mg, 47.19 μmol, 1.00 eq) in DCM (1.00 mL) was added DAST (45.64 mg, 283.14 μmol, 37.41 μL 6.00 eq) at −30° C. under N₂, the reaction mixture was stirred at 10° C. for 2 hours. TLC indicated the starting material was consumed completely and one major new spot with lower polarity was detected. The reaction mixture was quenched with water (10 mL) and then extracted with DCM (20 mL*3), the combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified via prep-TLC, followed by prep-HPLC (FA) to afford the title compound as white solid.

LCMS (M+1): 426/428. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=6.53, 2.63 Hz, 1H) 7.15-7.22 (m, 1H) 7.03-7.10 (m, 1H) 6.45 (s, 1H) 4.53-4.73 (m, 6H) 4.42 (dd, J=14.43, 6.78 Hz, 1H) 3.81-3.91 (m, 2H) 3.33 (s, 3H) 2.87 (t, J=5.71 Hz, 2H).

*Pure but unknown enantiomer.

Compounds 036, 037, 039, 040, 041, 042, 043, and 044 were prepared in a manner analogous to Compound 038.

Compound 036: 4-(fluoromethyl)-2-methyl-1-oxo-N-(3-(trifluoromethyl)phenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 442 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.72 (s, 1H) 7.59 (d, J=7.53 Hz, 1H) 7.41 (t, J=7.91 Hz, 1H) 7.30 (d, J=7.78 Hz, 1H) 6.71 (s, 1H) 4.54-4.76 (m, 6H) 4.42 (dd, J=14.43, 6.90 Hz, 1H) 3.81-3.94 (m, 2H) 3.33 (s, 3H) 2.88 (t, J=5.77 Hz, 2H).

Compound 037_E1: (S*)-N-(3-chlorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 408/410. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.55 (m, 1H) 7.18-7.25 (m, 2H) 7.00-7.05 (m, 1H) 6.49 (s, 1H) 4.54-4.73 (m, 6H) 4.42 (dd, J=14.49, 6.84 Hz, 1H) 3.82-3.91 (m, 2H) 3.33 (s, 3H) 2.87 (t, J=5.77 Hz, 2H).

*Pure but unknown enantiomer.

Compound 039_E1: (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 460. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.57-7.61 (m, 1H), 7.47-7.54 (m, 1H), 7.06 (t, J=9.4 Hz, 1H), 6.46 (s, 1H), 4.57-4.67 (m, 4H), 4.45-4.56 (m, 2H), 4.34 (dd, J=6.9, 14.5 Hz, 1H), 3.80 (q, J=5.7 Hz, 2H), 3.25 (s, 3H), 2.80 (t, J=5.7 Hz, 2H).

*Pure but unknown enantiomer.

Compound 040_E1: (S*)-N-(3-bromo-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 470/472. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.70 (dd, J=2.57, 5.96 Hz, 1H), 7.22-7.27 (m, 1H), 7.04 (t, J=8.53 Hz, 1H), 6.53 (s, 1H), 4.50-4.82 (m, 6H), 4.41 (dd, J=6.90, 14.43 Hz, 1H), 3.86 (q, J=5.56 Hz, 2H), 3.32 (s, 3H), 2.86 (t, J=5.71 Hz, 2H).

*Pure but unknown enantiomer.

Compound 041_E1: (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 471/473. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.14-8.18 (m, 1H), 8.07 (d, J=5.5 Hz, 1H), 6.96 (d, J=3.4 Hz, 1H), 4.77 (s, 2H), 4.53-4.72 (m, 4H), 4.42 (dd, J=6.7, 14.5 Hz, 1H), 3.88 (t, J=5.9 Hz, 2H), 3.33 (s, 3H), 2.90 (t, J=5.7 Hz, 2H).

*Pure but unknown enantiomer.

Compound 042_E1: (S*)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 417. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.71-7.81 (m, 1H), 7.53-7.64 (m, 1H), 7.15 (s, 1H), 6.58 (s, H), 4.72 (d, J=2.08 Hz, 4H), 4.56 (d, J=5.14 Hz, 2H), 4.37-4.48 (m, 1H), 3.80-3.93 (m, 2H), 3.33 (s, 3H), 2.88 (t, J=5.81 Hz, 2H).

*Pure but unknown enantiomer.

Compound 043_E1: (S*)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 406 ¹H NMR (CHLOROFORM-d, 400 MHz): δ=7.16 (d, J=2.9 Hz, 1H), 6.99-7.06 (m, 1H), 6.85 (t, J=8.9 Hz, 1H), 6.28 (s, 1H), 4.46-4.65 (m, 7H), 4.34 (dd, J=14.4, 6.8 Hz, 1H), 3.79 (q, J=5.4 Hz, 2H), 3.25 (s, 3H), 2.79 (t, J=5.7 Hz, 2H), 2.18 ppm (d, J=1.3 Hz, 3H).

*Pure but unknown enantiomer.

Compound 044_E1: (S*)-N-(3-chloro-4,5-difluorophenyl)-4-(fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 444. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.34 (ddd, J=11.76, 6.43, 2.64 Hz, 1H) 7.21 (dt, J=5.30, 2.43 Hz, 1H) 6.49 (s, 1H) 4.54-4.73 (m, 6H) 4.42 (dd, J=14.49, 6.96 Hz, 1H) 3.81-3.91 (m, 2H) 3.33 (s, 3H) 2.87 (t, J=5.71 Hz, 2H).

*Pure but unknown enantiomer.

Compound 045: N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 3-chloro-4-fluoro-N-methyl-aniline (Intermediate 2, 45.00 mg, 229.53 μmol, 1.00 eq, HCl) and triphosgene (34.06 mg, 114.77 μmol, 0.50 eq) in DCM (3.00 mL) was added TEA (116.13 mg, 1.15 mmol, 159.08 μL 5.00 eq) dropwise. The resulting mixture was stirred for 0.5 h at 0° C. and then stirred at 20° C. for 0.5 hr. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (Intermediate 1, 66.27 mg, 229.53 μmol, 1.00 eq, HCl) was added portionwise at 0° C., then warmed back to 20° C. and stirred for 1 hr. LCMS showed starting material consumed and 77.5% product was formed. Two batches of reaction mixture were poured into H₂O (5 mL), and extracted with DCM (3*5 ml). The combined organic phase was dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain the title compound (70 mg, 84.92 μmol, 99.77% purity) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.33 (dd, J=2.70, 6.46 Hz, 1H), 7.19-7.26 (m, 1H), 7.12-7.18 (m, 1H), 4.43-4.55 (m, 2H), 4.23-4.36 (m, 3H), 3.66-3.75 (m, 1H), 3.55-3.66 (m, 3H), 3.31 (s, 6H), 3.26 (s, 3H), 3.18 (s, 3H). LCMS [M+1]: 438.

Compound 046: N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2,8,8-trimethyl-4,5,8,9,10,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one

To a solution of tert-butyl 4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 3, 43.00 mg, 113.03 μmol, 1.00 eq) in DCM (300.00 μL was added a solution of TFA (462.00 mg, 4.05 mmol, 300.00 μL 35.85 eq) in DCM (300.00 μL at 0° C., the reaction mixture was stirred at 10° C. for one hour. TLC indicated starting material was consumed completely. The solvent was removed on a rotary evaporator to afford the title compound (40.00 mg, crude, TFA) as yellow oil. The product was used in the next step directly without further purification.

Step 2. N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a mixture of 4-(hydroxymethyl)-2,8,8-trimethyl-4,5,8,9,10,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one (40.00 mg, 101.43 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (41.06 mg, 405.73 μmol, 56.24 μL 4.00 eq), followed by phenyl N-(3-chlorophenyl)carbamate (25.12 mg, 101.43 μmol, 1.00 eq), the reaction mixture was stirred at 10° C. for 16 hours. LCMS showed the starting material was consumed completely and about 50% of desired compound was detected. The mixture was extracted with DCM (50 mL*3) and water (30 mL), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (28.00 mg, 63.24 μmol, 62.35% yield, 98% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (s, 1H) 7.18-7.24 (m, 2H) 7.00-7.02 (d, J=7.78 Hz, 1H) 6.64 (s, 1H) 4.71 (s, 2H) 4.52-4.56 (m, 2H) 4.38-4.41 (m, 1H) 3.85-3.86 (m, 1H) 3.76-3.77 (m, 1H) 3.52-3.62 (m, 2H) 3.30 (s, 3H) 2.18 (brs, 1H) 1.34-1.36 (d, J=4.64 Hz, 6H).

LCMS: 434/436 [M+1].

Compound 047: N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of tert-butyl 4-(hydroxymethyl)-2,8-dimethyl-1-oxo-1,2,4,5,8,9-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(11H)-carboxylate (Intermediate 4, 60.00 mg, 163.75 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.32 g, 11.58 mmol, 857.16 μL 70.70 eq). The mixture was stirred at 15° C. for 1 hr. TLC (PE:EA=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to afford 4-(hydroxymethyl)-2,8-dimethyl-4,5,8,9,10,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one (64.00 mg, 168.28 μmol, 102.77% yield, TFA) as yellow oil. The resulting oil was dissolved with DCM (5.00 mL), and added TEA (82.48 mg, 815.10 μmol, 112.99 μL 5.00 eq) followed by phenyl N-(3-chlorophenyl)carbamate (40.38 mg, 163.02 μmol, 1.00 eq). The mixture was stirred at 15° C. for 16 hr. LCMS showed major product. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (25.00 mg, 59.25 μmol, 36.34% yield, 99.5% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.56 (s, 1H), 7.19-7.27 (m, 2H), 7.03 (d, J=7.5 Hz, 1H), 6.60 (brs, 1H), 4.72-4.86 (m, 1H), 4.51-4.69 (m, 3H), 4.33-4.48 (m, 1H), 4.07-4.19 (m, 1H), 3.67-3.93 (m, 2H), 3.33 (s, 3H), 3.24 (ddd, J=8.3, 13.2, 17.4 Hz, 1H), 3.10 (d, J=6.7 Hz, 1H), 2.07 (brs, 1H), 1.36 (dd, J=2.3, 6.8 Hz, 1H). LCMS: 420/422 [M+1].

Compound 048: N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methylmethanesulfonate

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 500.00 mg, 1.18 mmol, 1.00 eq) in DCM (4.00 mL) was added Et₃N (716.43 mg, 7.08 mmol, 981.40 μL 6.00 eq) followed by MsCl (540.68 mg, 4.72 mmol, 365.32 μl 4.00 eq) at 15° C. The resulting mixture was stirred for 20 hours at 25° C. TLC (Dichloromethane/Methanol=10/1) showed the starting material consumed nearly and major desired product was generated. The reaction mixture was diluted with dichloromethane (30 mL), and washed with 1N HCl (30 mL*2) and brine (30 mL). The organic layer was dried with Na₂SO₄, and concentrated to give the title compound (590.00 mg, 1.02 mmol, 86.67% yield, 87% purity) as a yellow solid.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methylmethanesulfonate (150.00 mg, 298.85 μmol, 1.00 eq) in DMF (8.00 mL) was added NaSMe (125.68 mg, 1.79 mmol, 114.25 μL 6.00 eq). The resulting mixture was stirred for 16 hours at 15° C. TLC (Dichloromethane/Methanol=10/1) showed the starting material consumed nearly and desired product was generated mainly. The reaction mixture was diluted with EtOAc (30 mL) and washed with water (30 mL*2) and brine (30 mL). The organic layer was dried with Na₂SO₄, and concentrated tin vacuo. The residue was purified by column chromatography (Dichloromethane:Methanol=20:1-10:1) to give 145.00 mg of the desired product with 70.5% purity as a yellow liquid, 30 mg of which was further purified via Prep-HPLC (TFA) to give 14.81 mg of the title compound with 98% purity. ¹H NMR: (CDCl₃, 400 MHz) δ=7.57-7.59 (m, 1H), 7.28-7.30 (m, 1H), 7.13 (t, J=9.20 Hz, 1H), 4.84 (s, 2H), 4.59-4.71 (m, 2H), 4.42-4.45 (m, 1H), 3.80-3.84 (t, J=6.00 Hz, 2H), 3.31 (s, 3H), 2.81-2.84 (m, 3H), 2.67-2.70 (m, 1H), 2.19 (s, 3H). LCMS [M+1]: 454.1

Compound 049_E1: (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of N-(3-chloro-4-fluoro-phenyl)-2-methyl-4-(methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 048, 80.00 mg, 123.37 μmol, 1.00 eq) in DCM (5.00 mL) was added m-CPBA (29.27 mg, 135.71 μmol, 80% purity, 1.10 eq) at 15° C. The resulting mixture was stirred for 16 hours at 30° C. TLC (Dichloromethane/Methanol=10/1) and LCMS showed the starting material was consumed completely and sulfone and sulfoxide were generated. The reaction mixture was diluted with dichloromethane (20 mL), then washed with water (10 mL), brine (10 mL), dried with Na₂SO₄, filtered, concentrated in vacuo. The residue was purified by Prep-TLC (Dichloromethane/Methanol=15/l), followed by prep-HPLC to 9.77 mg of Compound 050 and 29.09 mg of racemic Compound 049. 29.09 mg of racemic Compound 049 was separated by two rounds of SFC, and further purified by prep-HPLC (TFA condition) to give 4 enantiomers: Compound 049_E1 (6.86 mg), Compound 049_E2 (5.78 mg); Compound 049_E3 (7.15 mg) and Compound 049_E4 (6.79 mg). ¹H NMR: (CDCl₃, 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.22 (m, 1H), 7.07 (t, J=9.20 Hz, 1H), 6.46 (s, 1H), 5.03-5.12 (m, 1H), 4.65-4.78 (m, 3H), 4.45 (dd, J=7.60 Hz, J=7.60 Hz, 1H), 3.75-3.96 (m, 2H), 3.34 (s, 3H), 2.85-3.05 (m, 4H), 2.69 (s, 3H).

* pure but unknown stereochemistry

Compound 049_E2: (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 049_E2 was separated from the mixture described above.

¹H NMR: (CDCl₃, 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.22 (m, 1H), 7.07 (t, J=9.20 Hz, 1H), 6.46 (s, 1H), 5.03-5.12 (m, 1H), 4.65-4.78 (m, 3H), 4.45 (dd, J=7.60 Hz, J=7.60 Hz, 1H), 3.75-3.96 (m, 2H), 3.34 (s, 3H), 2.85-3.05 (m, 4H), 2.69 (s, 3H).

* pure but unknown stereochemistry

Compound 049_E3: (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 049_E3 was separated from the mixture described above.

¹H NMR: (CDCl₃, 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.22 (m, 1H), 7.07 (t, J=9.20 Hz, 1H), 6.46 (s, 1H), 5.03-5.12 (m, 1H), 4.65-4.78 (m, 3H), 4.45 (dd, J=7.60 Hz, J=7.60 Hz, 1H), 3.75-3.96 (m, 2H), 3.34 (s, 3H), 2.85-3.05 (m, 4H), 2.69 (s, 3H).

* pure but unknown stereochemistry

Compound 049_E4: (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)-methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H) carboxamide

Compound 049_E4 was separated from the mixture described above.

¹H NMR: (CDCl₃, 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.22 (m, 1H), 7.07 (t, J=9.20 Hz, 1H), 6.46 (s, 1H), 5.03-5.12 (m, 1H), 4.65-4.78 (m, 3H), 4.45 (dd, J=7.60 Hz, J=7.60 Hz, 1H), 3.75-3.96 (m, 2H), 3.34 (s, 3H), 2.85-3.05 (m, 4H), 2.69 (s, 3H).

* pure but unknown stereochemistry

Compound 050: N-(3-chloro-4-fluorophenyl)-2-methyl-4-((methylsulfonyl)methyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 050 was separated from the mixture described above.

¹H NMR: (CDCl₃, 400 MHz) δ=7.53-7.57 (m, 1H), 7.15-7.20 (m, 1H), 7.07 (t, J=8.80 Hz, 1H), 6.45 (s, 1H), 5.12 (s, 1H), 4.65-4.78 (m, 3H), 4.53 (d, J=7.60 Hz, 1H), 3.75-3.90 (m, 3H), 3.32-3.45 (m, 3H), 3.27 (d, J=4.80 Hz, 1H), 3.03 (s, 3H), 2.88 (t, J=6.00 Hz, 2H). LCMS [M+1]: 486.3

Compound 051: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl methyl carbonate

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 50.00 mg, 117.97 μmol, 1.00 eq) in DCM (10.00 mL) was added Et₃N (119.37 mg, 1.18 mmol, 163.53 μL 10.00 eq) followed by methyl carbonochloridate (111.48 mg, 1.18 mmol, 91.38 μL 10.00 eq) under ice-water bath (maintaining the inner temperature between 5-10° C.). The resulting mixture was stirred for 2 hours at 30° C. TLC and LCMS showed the starting material was consumed, and the desired product was generated. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give the purified product (50.00 mg, 102.73 μmol, 87.08% yield, 99% purity) as a white solid. LCMS: 482.1 [M+1]. ¹H NMR: (CDCl₃, 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.23 (m, 1H), 7.05 (t, J=8.80 Hz, 1H), 6.43 (s, 1H), 4.65-4.75 (m, 3H), 4.55-4.63 (m, 1H), 4.35-4.45 (m, 2H), 4.21-4.31 (m, 1H), 3.75-3.89 (m, 5H), 3.31 (s, 3H), 2.86 (t, J=6.00 Hz, 2H).

Compounds 052, 053, 054, 055 and 056 were prepared in a manner analogous to Compound 051.

Compound 052: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl acetate

LCMS: 466.1 [M+1]. ¹H NMR: (CDCl₃, 400 MHz) δ=7.56-7.59 (m, 1H), 7.15-7.21 (m, 1H), 7.06 (t, J=8.80 Hz, 1H), 6.45 (s, 1H), 4.55-4.75 (m, 4H), 4.31-4.42 (m, 2H), 4.14-4.22 (m, 1H), 4.21-4.31 (m, 1H), 3.79-3.91 (m, 2H), 3.30 (s, 3H), 2.86 (t, J=6.40 Hz, 2H), 2.12 (s, 3H).

Compound 053: 10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl isopropyl carbonate

LCMS: 510 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.69, 6.48 Hz, 1H), 7.17-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.53 (s, 1H), 4.92 (m, J=6.24 Hz, 1H), 4.65-4.75 (m, 3H), 4.56-4.65 (m, 1H), 4.32-4.41 (m, 2H), 4.24 (dd, J=4.58, 11.92 Hz, 1H), 3.80-3.92 (m, 2H), 3.30 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 1.29-1.38 (m, 6H).

Compound 054: tert-butyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl) carbonate

LCMS: 546 [M+23], ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.55 (s, 1H), 4.65-4.77 (m, 3H), 4.56-4.64 (m, 1H), 4.27-4.41 (m, 2H), 4.18 (dd, J=4.65, 11.98 Hz, 1H), 3.77-3.93 (m, 2H), 3.30 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 1.51 (s, 9H).

Compound 055: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl pivalate

LCMS: 508 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.57 (dd, J=2.57, 6.48 Hz, 1H), 7.16-7.24 (m, 1H), 7.02-7.10 (m, 1H), 6.53 (s, 1H), 4.57-4.73 (m, 4H), 4.29-4.39 (m, 2H), 4.18-4.27 (m, 1H), 3.86 (t, J=5.81 Hz, 2H), 2.86 (t, J=5.75 Hz, 2H), 1.24 (s, 9H).

Compound 056: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl ethyl carbonate

LCMS: 496 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.57 (dd, J=2.69, 6.48 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.52 (s, 1H), 4.65-4.76 (m, 3H), 4.56-4.65 (m, 1H), 4.32-4.43 (m, 2H), 4.21-4.30 (m, 3H), 3.77-3.95 (m, 2H), 3.31 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 1.35 (t, J=7.09 Hz, 3H).

Compound 057: (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl carbamate

To a solution of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 50.00 mg, 117.97 μmol, 1.00 eq) in DCM (8.00 mL) was added sodium cyanate (230.08 mg, 3.54 mmol, 30.00 eq) followed by CF₃COOH (403.53 mg, 3.54 mmol, 262.03 μL 30.00 eq) at 10° C. The resulting mixture was stirred for 48 hours at 30° C. LCMS and HPLC showed starting material/desired product=1/2. The reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC (TFA condition) to give the desired product (16.74 mg, 35.86 nmol, 30.40% yield) as a white solid. ¹H NMR: (MeOD, 400 MHz) δ=7.57-7.59 (m, 1H), 7.23-7.39 (m, 1H), 7.13 (t, J=9.20 Hz, 1H), 4.65-4.75 (m, 3H), 4.59-4.64 (m, 1H), 4.33-4.41 (m, 1H), 4.25-4.32 (m, 1H), 4.13-4.20 (m, 1H), 3.82 (t, J=6.00 Hz, 2H), 3.31 (s, 3H), 2.82 (t, J=6.40 Hz, 2H). LCMS: 467 [M+1].

Compound 058: N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq) in DCM (2.00 mL) was added TEA (358.95 mg, 3.55 mmol, 491.72 μL 2.50 eq) and MsCl (211.30 mg, 1.84 mmol, 142.77 μL 1.30 eq). Then the mixture was stirred 20° C. for 2 hr. TLC (Ethyl acetate) showed the reaction was complete. The reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to give tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (600.00 mg, 1.39 mmol, 98.16% yield) was obtained as yellow solid, which was used in the next step without further purification.

Step 2. tert-butyl 4-[(dimethylamino) methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate and tert-butyl 4-(dimethylcarbamoyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (50.00 mg, 116.15 μmol, 1.00 eq) and Me₂NH (94.71 mg, 1.16 mmol, 106.42 μL 10.00 eq, HCl) in DMF (3.00 mL) was added K₂CO₃ (160.53 mg, 1.16 mmol, 161.00 μL 10.00 eq). The mixture was stirred at 80° C. for 12 hr. LCMS showed the starting material was consumed and 19% 3 and 65% 3a were generated. The mixture was filtered and the filtrate was concentrated in vacuum. The crude was purified by prep-TLC (Dichloromethane:Methanol=10:1) to give the first titled compound (9.00 mg, 22.53 μmol, 19.40% yield, 95% purity) as the colorless oil, and the second titled compound (15.00 mg, 35.42 μmol, 30.50% yield) was obtained as colorless oil.

tert-butyl 4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

¹H NMR (400 MHz, CHLOROFORM-d) δ 4.62-4.70 (m, 2H), 4.47-4.59 (m, 2H), 4.23-4.35 (m, 1H), 3.58-3.86 (m, 2H), 3.19-3.36 (m, 3H), 2.77 (t, J=5.44 Hz, 2H), 2.41-2.67 (m, 2H), 2.34 (s, 6H), 1.49 (s, 9H).

tert-butyl 4-(dimethylcarbamoyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

¹H NMR (400 MHz, CHLOROFORM-d) δ 4.51-4.72 (m, 4H), 4.27-4.39 (m, 2H), 4.15-4.25 (m, 1H), 3.71 (s, 2H), 3.28 (s, 3H), 2.92 (d, J=17.73 Hz, 5H), 2.70-2.80 (m, 2H), 1.48 (s, 9H).

Step 3, 4-[(dimethylamino)methyl]-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (67.00 mg, 176.57 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 152.99 eq). The mixture was stirred at 15° C. for 30 min. TLC (ethyl acetate) showed the reaction was complete. The mixture was evaporated to give the crude title compound (80.00 mg, crude, TFA) as colorless oil, which was used in the next step without further purification.

Step 4. N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 4-[(dimethylamino)methyl]-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (49.00 mg, 175.41 μmol, 1.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (46.60 mg, 175.41 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (53.25 mg, 526.23 μmol, 72.95 μL 3.00 eq). The mixture was stirred at 15° C. for 16 hr. LCMS showed the reaction was completed. The mixture was evaporated in vacuo. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 5 u; mobile phase: [water (0.225% FA)-ACN]; B %: 11%-41%, 10 min) The title compound (48.00 mg, 106.24 μmol, 60.57% yield, 99.8% purity) was obtained as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.53 (s, 1H), 4.77 (quin, J=5.81 Hz, 1H), 4.70 (s, 2H), 4.59 (dd, J=5.93, 14.61 Hz, 1H), 4.34 (dd, J=4.89, 14.67 Hz, 1H), 3.77-3.96 (m, 2H), 3.32 (s, 3H), 2.86 (t, J=5.75 Hz, 2H), 2.73 (d, J=6.72 Hz, 2H), 2.48 (s, 6H). LCMS: 451[M+1].

Compound 059: [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl N,N-dimethylcarbamate

Step 1. (2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-4-yl)methyl N,N-dimethylcarbarnate

To a solution of tert-butyl 4-(dimethylcarbamoyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (As described above, 55.00 mg, 129.88 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (14.81 mg, 129.88 μmol, 9.62 μL 1.00 eq). Then the mixture was stirred at 10° C. for 30 min. TLC (ethyl acetate) showed the reaction was complete. The mixture was evaporated to give the title compound (70.00 mg, crude, TFA) was obtained as colorless oil.

Step 2. [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl N,N-dimethylcarbamate

To a solution of (2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl)methyl N,N-dimethylcarbamate (42.00 mg, 96.03 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (25.51 mg, 96.03 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (29.15 mg, 288.09 μmol, 39.93 μL 3.00 eq). Then the mixture was stirred at 15° C. for 12 hr. LCMS showed the reaction was complete. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 35%-65%, 10 min) to give the title compound (35.00 mg, 69.17 μmol, 72.02% yield, 97.8% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=2.69, 6.48 Hz, 1H), 7.17-7.24 (m, 1H), 7.02-7.08 (m, 1H), 6.56 (s, 1H), 4.64-4.73 (m, 3H), 4.55-4.63 (m, 1H), 4.32-4.40 (m, 2H), 4.21-4.27 (m, 1H), 3.86 (t, J=5.87 Hz, 2H), 3.30 (s, 3H), 2.93 (d, J=16.99 Hz, 6H), 2.86 (t, J=5.69 Hz, 2H). LCMS: 495[M+1].

Compound 060_E1: (S*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 2-ethyl-4-(hydroxymethyl)-4,5,8,9,10,11 hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A solution of tert-butyl 2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 5, 51.00 mg, 139.19 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL 48.52 eq). Then the mixture was stirred at 10° C. for 1 hr. LCMS showed the reaction was completed. The mixture was evaporated to give the title compound (60.00 mg, crude) as the colorless oil which was used in the next step directly without further purification.

Step 2. (S*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 2-ethyl-4-(hydroxymethyl)-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (60.00 mg, 135.19 μmol, 1.00 eq) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (22.27 mg, 83.82 μmol, 0.62 eq) in DCM (3.00 mL) was added TEA (27.36 mg, 270.38 μmol, 37.48 μL 2.00 eq). Then the mixture was stirred at 10° C. for 16 hr. LCMS showed the reaction was completed. The mixture was concentrated in vacuo. The residue was purified by Prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase: [water (0.225% FA)-ACN]; B %: 30%-60%, 10 min). N-(3-chloro-4-fluoro-phenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (34.00 mg, 76.88 μmol, 56.87% yield, 99% purity) was obtained as white solid. 30 mg of the racemate was separated by SFC (column: Phenomenex Synergi Max-RP 250*80 10 u; mobile phase: [Base-MeOH]; B %: 40%-40%, 3 MIN; 90 min), followed by prep-HPLC to give both enantiomers (each 12.00 mg, 27.41 μmol, 40.00% yield) as white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.62 (m, 1H), 7.16-7.24 (m, 1H), 7.02-7.12 (m, 1H), 6.53 (s, 1H), 4.63-4.79 (m, 2H), 4.43-4.60 (m, 3H), 3.78-3.96 (m, 4H), 3.74 (dd, J=4.52, 11.54 Hz, 1H), 3.64 (qd, J=6.84, 13.85 Hz, 1H), 2.85 (t, J=5.40 Hz, 2H), 2.03 (s, 1H), 1.34 (t, J=7.03 Hz, 3H). LCMS: 438/440[M+1].

*Pure but unknown enantiomer.

Compound 060_E2: (R*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4-(hydroxymethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 060_E2 was isolated from the above-described mixture.

¹H NMR (400 MHz, CHLOROFORM-d) δ 7.55 (dd, J=2.51, 6.40 Hz, 1H), 7.15-7.23 (m, 1H), 6.99-7.09 (m, 1H), 6.63 (s, 1H), 4.62-4.77 (m, 2H), 4.44-4.60 (m, 3H), 3.76-3.94 (m, 4H), 3.69-3.76 (m, 1H), 3.63 (qd, J=7.00, 14.13 Hz, 1H), 2.84 (t, J=5.58 Hz, 2H), 2.29 (s, 1H), 1.33 (t, J=7.09 Hz, 3H). LCMS: 438/440[M+1].

*Pure but unknown enantiomer.

Compound 061: N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2,5-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 2,5-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 7, 30.00 mg, 89.18 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 302.90 eq). The reaction 193 mixture was stirred at 15° C. for 12 hr. LCMS showed the starting material was consumed completely and −84% desired product was detected. The reaction mixture was concentrated in vacuo to give the title compound (35.00 mg, crude, TFA) as a off-white solid. LCMS: 237 [M+1].

Step 2, N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 2,5-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-1-one (35.00 mg, 99.92 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (26.00 mg, 97.92 μmol, 0.98 eq) in DCM (3.00 mL) was added TEA (73.00 mg, 721.42 μmol, 100.00 μL 7.22 eq). The reaction mixture was stirred at 30° C. for 12 hr. LCMS showed compound 4 was consumed completely and ˜75% desired product was detected. The reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (HCl) to give the title compound (15.00 mg, 34.21 μmol, 34.23% yield, 93% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) 7.49-7.65 (m, 1H), 7.19 (s, 1H), 7.00-7.09 (m, 1H), 6.61 (s, 1H), 4.62-4.81 (m, 4H), 4.53 (dd, J=5.01, 11.62 Hz, 1H), 4.04 (dd, J=8.25, 11.43 Hz, 1H), 3.86 (s, 2H), 3.33 (s, 3H), 2.88 (s, 2H), 1.64 (d, J=6.36 Hz, 3H). LCMS: 408 [M+1].

Compound 062: N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 2,4-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

Tert-butyl 2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 8, 50.00 mg, 148.64 μmol, 1.00 eq) was dissolved in TFA (5.13 g, 45.02 mmol, 3.33 mL, 302.90 eq). The mixture was stirred at 10° C. for 1 hr. TLC (PE:EA=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to obtain the title compound (53.00 mg, crude, TFA) as colorless oil.

Step 2, N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,4,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 2,4-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (45.00 mg, 128.46 μmol, 1.00 eq, TFA) in DCM (5.00 mL) was added TEA (65.00 mg, 642.32 μmol, 89.04 μL 5.00 eq) followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (34.13 mg, 128.46 μmol, 1.00 eq). The mixture was stirred at 30° C. for 16 hr. LCMS showed one main peak with desired Ms detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (HCl) to get N-(3-chloro-4-fluoro-phenyl)-2,4-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 062 (43.00 mg, 105.23 μmol, 81.91% yield, 99.8% purity) as white solid.

¹H NMR (400 MHz, METHANOL-d₄) δ=7.60 (dd, J=2.5, 6.7 Hz, 1H), 7.28-7.36 (m, 1H), 7.15 (t, J=8.9 Hz, 1H), 4.74 (s, 2H), 4.65-4.69 (m, 1H), 4.59 (dd, J=5.3, 14.4 Hz, 1H), 4.24 (dd, J=5.3, 14.5 Hz, 1H), 3.85 (t, J=5.6 Hz, 2H), 3.30 (s, 3H), 2.85 (t, J=5.6 Hz, 2H), 1.29-1.37 (m, 3H). LCMS: 408[M+1].

Compound 063 was prepared in a manner analogous to Compound 062.

Compound 063: N-(3-chlorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazole[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

¹H NMR (400 MHz, METHANOL-d₄) δ=7.54 (t, J=2.0 Hz, 1H), 7.29-7.35 (m, 1H), 7.21-7.27 (m, 1H), 7.02 (d, J=7.8 Hz, 1H), 4.74 (s, 2H), 4.64-4.71 (m, 1H), 4.59 (dd, J=5.7, 14.4 Hz, 1H), 4.24 (dd, J=5.5, 14.3 Hz, 1H), 3.85 (t, J=5.9 Hz, 2H), 3.30 (s, 3H), 2.85 (t, J=5.8 Hz, 2H), 1.34 (d, J=6.2 Hz, 3H). LCMS: 390[M+1].

Compound 064: N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-5,8,9,11-tetrahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2,4,4-trimethyl-8,9,10,11-tetrahydro-5H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 2,4,4-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 9, 70.00 mg, 199.77 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 67.61 eq). The mixture was stirred at 10° C. for 1 hr. TLC (PE:EA=0:1) showed Compound 8 consumed. The mixture was concentrated in vacuum to get the title compound (73.00 mg, crude, TFA) as yellow oil.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo-5,8,9,11-tetrahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 2,4,4-trimethyl-8,9,10,11-tetrahydro-5H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-1-one (73.00 mg, 200.37 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (53.23 mg, 200.37 μmol, 1.00 eq) in DCM (10.00 mL) was added TEA (101.38 mg, 1.00 mmol, 138.88 μL 5.00 eq). The mixture was stirred at 10° C. for 16 hr. LCMS showed 50% desired product detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get the title compound (50.20 mg, 118.29 μmol, 59.03% yield, 99.4% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.64, 6.53 Hz, 1H), 7.21 (ddd, J=2.76, 4.02, 8.91 Hz, 1H), 7.04-7.11 (m, 1H), 6.48 (s, 1H), 4.71 (s, 2H), 4.25 (s, 2H), 3.88 (t, J=5.77 Hz, 2H), 3.29 (s, 3H), 2.88 (t, J=5.77 Hz, 2H), 1.39 (s, 6H). LCMS (M+1): 422.

Compound 065: N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of tert-butyl4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 50.00 mg, 141.89 μmol, 1.00 eq) in DMF (4.00 mL) was added NaH (8.51 mg, 212.83 μmol, 60% purity, 1.50 eq) in one portion at −40° C. under N₂. The mixture was stirred at −40˜−10° C. for 30 min, then Mel (40.28 mg, 283.78 μmol, 17.67 μL 2.00 eq) was added to the mixture. The mixture was stirred at 0° C. for 1 hour. TLC (ethyl acetate:petroleum ether=2:1) showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (5 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-TLC (ethyl acetate:petroleum ether=2:1) to afford the title compound (30.00 mg, 72.05 μmol, 50.78% yield, 88% purity) as a yellow solid. LCMS: 367 [M+1].

Step 2. Preparation of 4-(methoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a mixture of tert-butyl 4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (30.00 mg, 81.88 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (616.00 mg, 5.40 mmol, 400.00 μL 65.98 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hr. LCMS showed the reaction was completed. The residue was concentrated in vacuum to afford (31.34 mg, crude, TFA) as yellow solid. LCMS: 267 [M+1].

Step 3. Preparation of N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a mixture of 4-(methoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (31.14 mg, 81.88 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (21.75 mg, 81.88 μmol, 1.00 eq) in DCM (4.00 mL) was added TEA (82.85 mg, 818.78 μmol, 113.50 μL 10.00 eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (24.00 mg, 54.16 μmol, 66.14% yield, 98.8% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) 7.53-7.63 (m, 1H), 7.14-7.23 (m, 1H), 7.06 (s, 1H), 6.46 (s, 1H), 4.70 (s, 2H), 4.48-4.65 (m, 2H), 4.41 (s, 1H), 3.86 (d, J=12.67 Hz, 2H), 3.57-3.67 (m, 1H), 3.49-3.56 (m, 1H), 3.44 (s, 3H), 3.31 (s, 3H), 2.82-2.93 (m, 2H). LCMS: 438 [M+1].

Compound 066: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one

To a mixture of tert-butyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 10, 55.00 mg, 170.62 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (616.00 mg, 5.40 mmol, 400.00 μL 31.66 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hr. TLC (dichloromethane:methanol=10:1) showed the reaction was completed. The residue was concentrated to afford (57.37 mg, 170.61 μmol, 100.00% yield, TFA) as a yellow oil.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

To a mixture of 2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5] oxadiazepin-1-one (57.37 mg, 170.61 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (45.33 mg, 170.61 μmol, 1.00 eq) in DCM (4.00 mL) was added TEA (172.64 mg, 1.71 mmol, 236.49 μL 10.00 eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (42.00 mg, 105.05 μmol, 61.58% yield, 98.5% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) 7.55-7.62 (m, 1H), 7.16-7.24 (m, 1H), 7.02-7.11 (m, 1H), 6.48-6.56 (m, 1H), 4.71 (s, 2H), 4.52-4.60 (m, 2H), 4.36-4.45 (m, 2H), 3.82-3.93 (m, 2H), 3.31 (s, 3H), 2.87 (s, 2H). LCMS: 394 [M+1].

Compound 067: 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. 2-allyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 2-allyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 12, 30.00 mg, 86.11 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL 78.43 eq), the reaction mixture was stirred at 10° C. for one hour. TLC indicated Compound 7 was consumed completely, and one major new spot with larger polarity was detected. The solvent was removed on a rotary evaporator to give the title compound (30.00 mg, crude, TFA) as a yellow oil. The crude product was used in next step directly without purification.

Step 2, 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

To a solution of 2-allyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5] oxadiazepin-1-one (30.00 mg, 82.80 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (33.52 mg, 331.22 μmol, 45.91 μL 4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (22.00 mg, 82.80 μmol, 1.00 eq). The reaction mixture was stirred at 10° C. for 16 hours. LCMS showed Compound 8 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (30 mL*2) and water (20 mL), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. Further purification by prep-HPLC(FA) to give the title compound (32.60 mg, 75.68 μmol, 91.41% yield, 97.47% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.56-7.58 (dd, J=6.54, 2.63 Hz, 1H) 7.18-7.21 (m, 1H) 7.03-7.07 (m, 1H) 6.55 (s, 1H) 5.92-5.97 (ddt, J=16.93, 10.30, 6.31, 6.31 Hz, 1H) 5.32-5.34 (m, 2H) 4.71 (s, 2H) 4.54-4.57 (m, 2H) 4.36-4.39 (m, 2H) 4.28-4.30 (d, J=6.36 Hz, 2H) 3.85-3.87 (t, J=5.81 Hz, 2H) 2.85-2.87 (t, J=5.75 Hz, 2H). LCMS: 420/422 [M+1].

Compound 068: N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl 2-allyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-c][1,2,5]oxadiazepine-10-carboxylate (Compound 067, 40.00 mg, 114.81 μmol, 1.00 eq) and Pd/C (20.00 mg, 10% purity) in MeOH (20.00 mL) was stirred under H₂ (15 psi) at 10° C. for 16 hours. LCMS showed Compound 7 was consumed completely and one main peak with desired MS was detected. The reaction mixture was filtered and the filter was concentrated to give the title compound (38.00 mg, 108.44 μmol, 94.46% yield) as a yellow oil. LCMS: 373 [M+23].

Step 2, 2-propyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate (38.00 mg, 108.44 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 124.55 eq). The reaction mixture was stirred at 10° C. for one hour. TLC indicated Compound 9 was consumed completely, and one major new spot with larger polarity was detected. The solvent was removed on a rotary evaporator to give (38.00 mg, crude, TFA) as a yellow oil, which was used in next step directly without further purification.

Step 3. N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

To a solution of 2-propyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c] [1,2,5]oxadiazepin-1-one (38.00 mg, 104.30 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (42.22 mg, 417.20 μmol, 57.84 μL 4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (27.71 mg, 104.30 μmol, 1.00 eq). The reaction mixture was stirred at 10° C. for 16 hours. LCMS showed Compound 10 was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (30 mL*2) and water (20 mL), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purification by prep-HPLC(FA) to give the title compound (35.39 mg, 82.06 μmol, 78.67% yield, 97.81% purity) was obtained as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) 8=7.56-7.58 (dd, J=6.53, 2.63 Hz, 1H) 7.17-7.19 (m, 1H) 7.03-7.08 (m, 1H) 6.52 (s, 1H) 4.70 (s, 2H) 4.54-4.57 (m, 2H) 4.38-4.41 (m, 2H) 3.85-3.88 (t, J=5.77 Hz, 2H) 3.64-3.68 (m, 2H) 2.85-2.87 (t, J=5.77 Hz, 2H) 1.74-1.83 (m, J=7.38 Hz, 2H) 1.00-1.04 (t, J=7.40 Hz, 3H).

LCMS: 422/424 [M+1].

Compound 069_E1: (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a mixture of tert-butyl 4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 14, 100.00 mg, 272.92 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (616.00 mg, 5.40 mmol, 400.00 μL 19.80 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hr. TLC and LCMS showed the reaction was completed. The mixture was concentrated in vacuum to afford the title compound (103.80 g, crude, TFA) as a yellow oil.

LCMS: 267 [M+1].

Step 2, (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a mixture of 4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (103.80 mg, 272.93 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (72.51 mg, 272.93 μmol, 1.00 eq) in DCM (6.00 mL) was added TEA (276.18 mg, 2.73 mmol, 378.32 μL 10.00 eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMS and TLC (dichloromethane:methanol=10:1) showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (dichloromethane:methanol=100/1, 50/1) to afford the title compound (98.00 mg, 218.90 μmol, 80.20% yield, 97.8% purity) as a yellow solid, which was resolved by SFC (Instrument: SFC Waters_80_Q Column: OD-10 um. Mobile phase: A for CO₂ and B for Methanol (0.1% NH₃H₂O) Isocratic: B 25%. Flow rate: 55 mL/min. Back pressure: 100 bar. Column temperature: 35° C.; Wavelength: 220 nm) to give two fractions. The first fraction was separated by SFC (Instrument: SFC Thar_80_Q. Column: OJ-5 um. Mobile phase: A for CO₂ and B for Isopropanol (0.1% NH₃H₂O). Isocratic: B 25%. Flowrate: 55 mL/min. Backpressure: 100 bar. Column temperature: 35° C. Wavelength: 220 nm) to give Compound 070_E1(8.68 mg, 95.8% purity) and Compound 069_E2 (20.43 mg, 98.0% purity) as a white solid. LCMS: 438 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 7.55-7.63 (m, 1H), 7.16-7.24 (m, 1H), 7.02-7.10 (m, 1H), 6.43-6.52 (m, 1H), 5.09-5.21 (m, 1H), 4.80-4.93 (m, 1H), 4.52-4.65 (m, 2 H), 4.33-4.50 (m, 2H), 3.74-3.96 (m, 2H), 3.34 (s, 3H), 2.98-3.10 (m, 1H), 2.63-2.74 (m, 1H), 1.82-1.99 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 069_E2: (4R*,9S*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Obtained from the above-described mixture.

LCMS: 438 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 7.53-7.64 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.12 (m, 1H), 6.42-6.50 (m, 1H), 5.07-5.18 (m, 1H), 4.77-4.86 (m, 1H), 4.38-4.66 (m, 4H), 3.71-3.93 (m, 2H), 3.33 (s, 3H), 2.97-3.10 (m, 1H), 2.68 (d, J=15.94 Hz, 1H), 1.85-1.98 (m, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

The second fraction was separated by SFC (Instrument: SFC Thar_80_Q. Column: OJ-5 um. Mobile phase: A for CO₂ and B for Methanol (0.1% NH₃H₂O). Isocratic: B 25%. Flow rate: 55 mL/min. Back pressure: 100 bar. Column temperature: 35° C. Wavelength: 220 nm) to give Compound 069_E3(15.37 mg, 97.3% purity) and Compound 069_E4 (21.86 mg, 99.26% purity) as white solid.

Compound 069_E3: (4R*,9R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 438 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 7.55-7.65 (m, 1H), 7.16-7.23 (m, 1H), 7.01-7.13 (m, 1H), 6.40-6.52 (m, 1H), 5.07-5.23 (m, 1H), 4.80-4.92 (m, 1H), 4.52-4.63 (m, 2H), 4.34-4.50 (m, 2H), 3.74-3.96 (m, 2H), 3.02 (d, J=5.77 Hz, 1H), 2.71 (s, 1H), 1.80-1.96 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 069_E4: (4S*,9R*)-N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 438 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 7.54-7.65 (m, 1H), 7.15-7.23 (m, 1H), 7.01-7.11 (m, 1H), 6.40-6.52 (m, 1H), 5.06-5.19 (m, 1H), 4.75-4.86 (m, 1H), 4.36-4.65 (m, 4H), 3.71-3.91 (m, 2H), 2.98-3.10 (m, 1H), 2.68 (d, J=15.69 Hz, 1H), 1.84-2.01 (m, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 070 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a mixture of tert-butyl 6-methyl-3-(methyl(oxetan-3-yloxy)carbamoyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (Intermediate 15, 40.00 mg, 109.17 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL 61.86 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hours. LCMS and TLC (dichloromethane:methanol=5:1) showed the reaction was completed. The reaction mixture was treated with TEA (1 mL) at −78° C. To the resulting mixture, was added phenyl N-(3-chlorophenyl)carbamate (27.04 mg, 109.16 μmol, 1.00 eq) in DCM (4.00 mL), followed by TEA (110.46 mg, 1.09 mmol, 151.32 μL 10.00 eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 5 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (17.00 mg, 40.17 μmol, 36.80% yield, 99.2% purity) as a white solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.79-8.94 (m, 1H), 7.62 (s, 1H), 7.35-7.42 (m, 1H), 7.22-7.29 (m, 1H), 6.93-7.02 (m, 1H), 5.13-5.22 (m, 1H), 4.96-5.07 (m, 1H), 4.80-4.91 (m, 1H), 4.38-4.60 (m, 2H), 4.09-4.34 (m, 2H), 3.44-3.69 (m, 2H), 3.23 (d, J=3.14 Hz, 3H), 2.84-2.95 (m, 1H), 2.58 (dd, J=4.20, 15.75 Hz, 1H), 1.09 (d, J=6.78 Hz, 3H). LCMS: 420 [M+1].

Compound 071: methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate

To a mixture of 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′: 3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate (Intermediate 16, 110.00 mg, 289.18 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL 23.35 eq) in one portion at 0° C. under N₂. The mixture was stirred at 0° C. for 2 hr. TLC (Dichloromethane:Methanol=10:1) showed the reaction was completed. The residue was concentrated in vacuum to give 2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (114.02 mg, 289.17 μmol, 1.00 eq, TFA) as yellow oil. The resulting oil and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (76.82 mg, 289.17 μmol, 1.00 eq) was dissolved in DCM (4.00 mL) and added TEA (292.61 mg, 2.89 mmol, 400.84 μL 10.00 eq) under N₂. The mixture was stirred at 25° C. for 10 hours. LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (60.00 mg, 131.99 μmol, 45.65% yield, 99.4% purity) as white solid.

LCMS: 452[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 7.57 (dd, J=2.64, 6.53 Hz, 1H), 7.15-7.24 (m, 1H), 7.01-7.11 (m, 1H), 6.48 (s, 1H), 4.92 (s, 2H), 4.74 (s, 1H), 4.50-4.68 (m, 2H), 3.90 (s, 3H), 3.86 (s, 2H), 3.40 (s, 3H), 2.77-2.98 (m, 2H).

Compound 072: N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

Step 1. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a mixture of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (Compound 071, 40.00 mg, 88.53 μmol, 1.00 eq) in DCE (4.00 mL) was added hydroxyl (trimethyl) stannane (80.04 mg, 442.65 μmol, 5.00 eq) in one portion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (30.00 mg, 65.13 μmol, 73.57% yield, 95.05% purity) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.52-7.58 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.11 (m, 1H), 6.47-6.56 (m, 1H), 4.84-5.03 (m, 1H), 4.59-4.78 (m, 1H), 3.85 (s, 1H), 3.40 (s, 3H), 2.87 (br d, J=5.50 Hz, 1H). LCMS: 438[M+1].

Step 2, N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (20.00 mg, 45.68 μmol, 1.00 eq) and NH₄Cl (24.44 mg, 456.82 μmol, 15.97 μL 10.00 eq) in DMF (3.00 mL) was added HOBt (9.26 mg, 68.52 μmol, 1.50 eq), PyBOP (35.66 mg, 68.52 μmol, 1.50 eq) and DIPEA (88.56 mg, 685.23 μmol, 119.67 μL 15.00 eq) in one portion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed, and desired product was detected. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (14.00 mg, 31.92 μmol, 69.88% yield, 99.6% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) 7.54-7.61 (m, 1H), 7.15-7.23 (m, 1H), 7.01-7.11 (m, 1H), 6.44-6.55 (m, 1H), 6.01-6.12 (m, 1H), 5.55-5.67 (m, 1H), 4.86-5.01 (m, 2H), 4.64-4.79 (m, 3H), 3.71-3.98 (m, 2H), 3.37 (s, 3H), 2.87 (s, 2H). LCMS: 437 [M+1].

Compound 073: N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

Step 1. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a mixture of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (Compound 071, 40.00 mg, 88.53 μmol, 1.00 eq) in DCE (4.00 mL) was added hydroxyl (trimethyl) stannane (80.04 mg, 442.65 μmol, 5.00 eq) in one portion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (30.00 mg, 65.13 μmol, 73.57% yield, 95.05% purity) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.58 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.11 (m, 1H), 6.47-6.56 (m, 1H), 4.84-5.03 (m, 1H), 4.59-4.78 (m, 1H), 3.85 (s, 1H), 3.40 (s, 3H), 2.87 (br d, J=5.50 Hz, 1H). LCMS: 438[M+1].

Step 2, N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (25.00 mg, 57.10 μmol, 1.00 eq) and methanamine (MeNH₂) (38.55 mg, 571.00 μmol, 10.00 eq, HCl) in DMF (2.00 mL) was added HATU (32.57 mg, 85.65 μmol, 1.50 eq) and DIPEA (110.69 mg, 856.50 μmol, 149.58 μL 15.00 eq) in one portion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was not reacted. The mixture was stirred at 30° C. for another 12 hours, LCMS showed the reaction was completed. The residue was poured into water (10 mL) and stirred for 2 min. The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to afford the title compound (20.00 mg, 44.01 μmol, 77.07% yield, 99.2% purity) as white solid. ¹H NMR (400 MHz, METHANOL-d₄) 7.56-7.64 (m, 1H), 7.26-7.36 (m, 1H), 7.08-7.21 (m, 1H), 4.98-5.05 (m, 1H), 4.74 (s, 4H), 3.72-3.96 (m, 2H), 3.34 (br. s., 4H), 2.80-2.90 (m, 2H), 2.76 (s, 3H). LCMS: 451 [M+1].

Compound 074: N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

Step 1. 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a mixture of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (Compound 071, 40.00 mg, 88.53 μmol, 1.00 eq) in DCE (4.00 mL) was added hydroxyl (trimethyl) stannane (80.04 mg, 442.65 μmol, 5.00 eq) in one portion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed. The residue was concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (30.00 mg, 65.13 μmol, 73.57% yield, 95.05% purity) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.58 (m, 1H), 7.16-7.23 (m, 1H), 7.02-7.11 (m, 1H), 6.47-6.56 (m, 1H), 4.84-5.03 (m, 1H), 4.59-4.78 (m, 1H), 3.85 (s, 1H), 3.40 (s, 3H), 2.87 (br d, J=5.50 Hz, 1H). LCMS: 438[M+1].

Step 2. N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (20.00 mg, 45.68 μmol, 1.00 eq) and N-methylmethanamine (18.62 mg, 228.40 μmol, 20.92 μL 5.00 eq, HCl) in DMF (5.00 mL) was added HATU (26.05 mg, 68.52 μmol, 1.50 eq) and DIPEA (88.56 mg, 685.20 μmol, 119.68 μL 15.00 eq) in one portion under N₂. The mixture was stirred at 30° C. for 12 hours. LCMS showed the reaction was completed, and the desired product was detected. The residue was poured into water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL*2). The combined organic phase was washed with brine (10 mL*2), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to afford the title compound (16.00 mg, 33.94 μmol, 74.29% yield, 98.6% purity) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) 7.53-7.66 (m, 1H), 7.22-7.39 (m, 1H), 7.06-7.19 (m, 1H), 5.28-5.40 (m, 1H), 4.89-4.95 (m, 1H), 4.72 (s, 2H), 4.54-4.66 (m, 1H), 3.70-3.97 (m, 2H), 3.21 (d, J=9.41 Hz, 6H), 3.02 (s, 3H), 2.77-2.89 (m, 2H). LCMS: 465 [M+1].

Compound 075: (9R)—N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

Step 1. (9R)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl (9R)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxylate (600.00 mg, 1.78 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (67.53 mmol, 5.00 mL, 37.94 eq). The mixture was stirred at 10° C. for 1 hr. TLC (petroleum ether:ethyl acetate=0:1) showed the starting material was consumed. The mixture was concentrated in vacuum to get the title compound (640.00 mg, crude, TFA) as yellow oil.

Step 2. (9R)—N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepine-10-carboxamide

To a solution of (9R)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-c][1,2,5]oxadiazepin-1-one (90.00 mg, 256.93 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (71.67 mg, 269.78 μmol, 1.05 eq) in DCM (2.00 mL) was added TEA (78.00 mg, 770.79 μmol, 106.85 μL 3.00 eq). The mixture was stirred at 30° C. for 1 h under N₂ atmosphere. TLC (DCM:MeOH=10:1) showed that (9R)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]oxadiazepin-1-one was consumed completely and one major spot formed. LCMS indicated that MS of desired product was detected. The mixture was diluted with DCM (10 mL) and washed with HCl (1%, 10 mL*2) and brine (10 mL*l). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (53.00 mg, 129.44 μmol, 50.38% yield, 99.6% purity) as a white solid. LCMS: 408 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.52-7.62 (m, 1H), 7.16-7.24 (m, 1H), 6.98-7.10 (m, 1H), 6.63 (s, 1H), 5.14 (quin, J=6.45 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.53-4.59 (m, 2H), 4.35-4.50 (m, 3H), 3.23-3.35 (m, 3H), 3.03 (dd, J=5.81, 15.83 Hz, 1H), 2.67 (d, J=15.77 Hz, 1H), 1.17 (d, J=6.97 Hz, 3H).

Compounds 076, 077, 078, 079, 080, and 081 were prepared in a manner analogous to Compound 075.

Compound 076: (R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 442 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=2.69, 6.11 Hz, 1H), 7.53-7.62 (m, 1H), 7.12 (t, J=9.41 Hz, 1H), 6.72 (s, 1H), 5.15 (quin, J=6.42 Hz, 1H), 4.87 (d, J=15.65 Hz, 1H), 4.52-4.60 (m, 2H), 4.45-4.52 (m, 1H), 4.36-4.45 (m, 2H), 3.25-3.37 (m, 3H), 3.04 (dd, J=5.87, 15.89 Hz, 1H), 2.69 (d, J=15.89 Hz, 1H), 1.18 (d, J=6.97 Hz, 3H).

Compound 077: (R)—N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 452/454. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.64-7.77 (m, 1H), 7.24-7.29 (m, 2H), 7.04 (t, J=8.50 Hz, 1H), 6.52-6.62 (m, 1H), 5.14 (quin, J=6.45 Hz, 1H), 4.79-4.92 (m, 1H), 4.53-4.62 (m, 2H), 4.37-4.51 (m, 3H), 3.31 (s, 3H), 3.04 (dd, J=5.81, 15.83 Hz, 1H), 2.68 (d, J=15.77 Hz, 1H), 1.17 (d, J=6.97 Hz, 3H).

Compound 078: (R)—N-(2-bromo-3-fluoropyridin-4-yl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 453/455. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.10-8.19 (m, 1H), 7.97-8.08 (m, 1H), 6.95-7.11 (m, 1H), 5.00-5.15 (m, 1H), 4.92 (d, J=15.77 Hz, 1H), 4.48-4.61 (m, 3H), 4.31-4.47 (m, 2H), 3.25-3.38 (m, 3H), 2.94-3.13 (m, 1H), 2.63-2.79 (m, 1H), 1.12-1.30 (m, 3H).

Compound 079: (R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 399 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.75 (dd, J=2.75, 5.44 Hz, 1H), 7.60 (ddd, J=2.81, 4.58, 9.11 Hz, 1H), 7.11 (t, J=8.68 Hz, 1H), 6.94 (s, 1H), 5.11 (quin, J=6.45 Hz, 1H), 4.88 (d, J=15.77 Hz, 1H), 4.52-4.62 (m, 2H), 4.32-4.50 (m, 3H), 3.29 (s, 3H), 2.94-3.08 (m, 1H), 2.61-2.73 (m, 1H), 1.17 (d, J=6.85 Hz, 3H).

Compound 080: (R)—N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 388 (M+1). ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.22-7.28 (m, 1H), 7.05-7.16 (m, 1H), 6.91 (t, J=8.99 Hz, 1H), 6.45 (br s, 1H), 5.15 (quin, J=6.45 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.51-4.60 (m, 2H), 4.29-4.50 (m, 3H), 3.22-3.38 (m, 3H), 2.96-3.10 (m, 1H), 2.67 (d, J=15.77 Hz, 1H), 2.24 (d, J=1.34 Hz, 3H), 1.17 (d, J=6.85 Hz, 3H).

Compound 081: (R)—N-(3-chloro-4,5-difluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 426. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.35 (ddd, J=63, 6.45, 11.95 Hz, 1H, 7.22 (td, J=2.43, 5.29 Hz, 1H), 6.70 (s, 1H), 5.12 (quin, J=6.45 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.52-4.61 (m, 2H), 4.34-4.49 (m, 3H), 3.24-3.35 (m, 3H), 2.95-3.10 (m, 1H), 2.59-2.77 (m, 1H), 1.09-1.22 (m, 3H).

Compound 083: (9R)—N-(4-fluoro-3-methyl-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 300.00 mg, (470.00 mg, 1.28 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (5.55 g, 48.67 mmol, 3.60 mL, 37.94 eq). The mixture was stirred at 10° C. for 1 hr. TLC (Ethyl acetate:MeOH=20:1) showed the starting material was consumed. The mixture was concentrated in vacuum to get the title compound (520.00 mg, crude, TFA) as yellow oil.

Step 2. (9R)—N-(4-fluoro-3-methyl-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a mixture of (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (138.00 mg, 362.85 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (146.87 mg, 1.45 mmol, 201.19 μL 4.00 eq), followed by phenyl N-(4-fluoro-3-methyl-phenyl)carbamate (88.99 mg, 362.85 μmol, 1.00 eq), the reaction mixture was stirred at 10° C. for 16 hours. LCMS showed the starting material was consumed completely and one main peak with desired MS was detected. The mixture was extracted with DCM (50 mL*2) and water (30 mL), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. 1/3 of the residue was purified by prep-HPLC (FA) to afford the title compound (32.00 mg, 99.24% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) d ppm δ=7.25 (d, J=2.45 Hz, 1H) 7.11 (dt, J=7.98, 3.90 Hz, 1H) 6.93 (t, J=8.99 Hz, 1H) 6.37 (s, 1H) 5.15 (quin, J=6.30 Hz, 1H) 4.86 (d, J=15.53 Hz, 1H) 4.52-4.62 (m, 2H) 4.34-4.49 (m, 2H) 3.75-3.93 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.77, 5.87 Hz, 1H) 2.68 (d, J=15.65 Hz, 1H) 2.26 (d, J=1.59 Hz, 3H) 1.82-2.04 (m, 1H) 1.17 (d, J=6.97 Hz, 3H). LCMS: 418 [M+1].

Compounds 069, 082, 084, 089, 090, and 091 were prepared in an analogous manner to Compound 083.

Compound 088: (9R)—N-(3-chloro-4-fluoro-phenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of (9R)—N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide, (Compound 069, 75.00 mg, 171.29 μmol, 1.00 eq) in DCM (5.00 mL) was added DAST (165.66 mg, 1.03 mmol, 135.79 μL 6.00 eq) at −30° C. under N₂, the reaction mixture was stirred at 15° C. for 2 hours. LCMS indicated that reactant was consumed completely and desired MS was detected. The mixture was washed with saturated NaHCO₃ (10 mL*1) and brine (10 mL*1). Then the organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (39.70 mg, 87.28 μmol, 50.96% yield, 96.7% purity) as a white solid.

Compounds 085, 086, and 087 were prepared in an analogous manner to Compound 088.

Compound 082_E1: (4S*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-di][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 472. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=6.05, 2.75 Hz, 1H) 7.55-7.62 (m, 1H) 7.14 (t, J=9.41 Hz, 1H) 6.56 (s, 1H) 5.15 (m, J=6.45 Hz, 1H) 4.88 (d, J=15.53 Hz, 1H) 4.54-4.62 (m, 2H) 4.36-4.51 (m, 2H) 3.77-3.93 (m, 2H) 3.34 (s, 3H) 3.05 (dd, J=15.96, 5.81 Hz, 1H) 2.70 (d, J=15.65 Hz, 1H) 1.89 (br. s., 1H) 1.19 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 082_E2: (4R*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 472. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.66-7.73 (m, 1H), 7.56-7.65 (m, 1H), 7.15 (s, 1H), 6.59 (s, 1H), 5.09-5.22 (m, 1H), 4.76-4.92 (m, 1H), 4.55 (s, 4H), 3.87 (s, 2H), 3.35 (s, 3H), 3.00-3.12 (m, 1H), 2.71 (d, J=15.65 Hz, 1H), 1.88-2.01 (m, 1H), 1.21 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 083_E1: (4S*,9R)—N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 418. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.25 (d, J=2.45 Hz, 1H) 7.11 (dt, J=7.98, 3.90 Hz, 1H) 6.93 (t, J=8.99 Hz, 1H) 6.37 (s, 1H) 5.15 (m, J=6.30 Hz, 1H) 4.86 (d, J=15.53 Hz, 1H) 4.52-4.62 (m, 2H) 4.34-4.49 (m, 2H) 3.75-3.93 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.77, 5.87 Hz, 1H) 2.68 (d, J=15.65 Hz, 1H) 2.26 (d, J=1.59 Hz, 3H) 1.82-2.04 (m, 1H) 1.17 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 083_E2: (4R*,9R)—N-(4-fluoro-3-methylphenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 472. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.24-7.27 (m, 1H), 7.08-7.15 (m, 1H), 6.89-6.97 (m, 1H), 6.37 (s, 1H), 5.04-5.25 (m, 1H), 4.82 (d, J=15.65 Hz, 1H), 4.29-4.65 (m, 4H), 3.68-3.93 (m, 2H), 3.33 (s, 3H), 2.94-3.13 (m, 1H), 2.56-2.74 (m, 1H), 2.26 (d, J=1.71 Hz, 3H), 1.89-2.01 (m, 1H), 1.18 (d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 084_E1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 429. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.79 (dd, J=5.44, 2.75 Hz, 1H) 7.54-7.61 (m, 1H) 7.15 (t, J=8.68 Hz, 1H) 6.50-6.58 (m, 1H) 5.08-5.19 (m, 1H) 4.78-4.91 (m, 1H) 4.53-4.61 (m, 2H) 4.37-4.51 (m, 2H) 3.78-3.93 (m, 2H) 3.35 (s, 3H) 3.04 (dd, J=15.83, 5.93 Hz, 1H) 2.70 (d, J=15.53 Hz, 1H) 1.78 (br. s., 1H) 1.17-1.22 (m, 3H).

*Pure but unknown enantiomer.

Compound 084_E2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 429. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.78 (br d, J=2.57 Hz, 1H), 7.59 (brd, J=4.40 Hz, 1H), 7.14 (brt, J=8.80 Hz, 1H), 6.62 (br d, J=16.14 Hz, 1H), 5.13 (br t, J=6.54 Hz, 1H), 4.82 (br d, J=15.77 Hz, 1H), 4.39-4.63 (m, 4H), 3.70-3.96 (m, 2H), 3.34 (s, 3H), 3.04 (br dd, J=5.99, 15.65 Hz, 1H), 2.70 (br d, J=16.02 Hz, 1H), 1.88 (br s, 1H), 1.20 (br d, J=6.97 Hz, 3H).

*Pure but unknown enantiomer.

Compound 085_E1: (4S*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 474. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=6.11, 2.69 Hz, 1H) 7.56-7.62 (m, 1H) 7.14 (t, J=9.35 Hz, 1H) 6.54 (s, 1H) 5.15 (m, J=6.45 Hz, 1H) 4.85 (d, J=15.65 Hz, 1H) 4.57-4.73 (m, 4H) 4.39-4.54 (m, 2H) 3.33 (s, 3H) 3.05 (dd, J=15.83, 5.81 Hz, 1H) 2.71 (d, J=16.02 Hz, 1H) 1.20 (d, J=6.97 Hz, 3H).

Compound 085_E2: (4R*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 474. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.65-7.73 (m, 1H), 7.56-7.63 (m, 1H), 7.14 (s, 1H), 6.54 (s, 1H), 5.08-5.22 (m, 1H), 4.82-4.92 (m, 1H), 4.37-4.79 (m, 6H), 3.34 (s, 3H), 2.99-3.13 (m, 1H), 2.62-2.79 (m, 1H), 1.19 (d, J=6.85 Hz, 3H).

*Pure but unknown enantiomer.

Compound 086_E1: (4S*,9R)—N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 420. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.25 (d, J=2.57 Hz, 1H) 7.11 (dt, J=7.89, 3.88 Hz, 1H) 6.93 (t, J=8.99 Hz, 1H) 6.34 (s, 1H) 5.09-5.19 (m, 1H) 4.79-4.89 (m, 1H) 4.56-4.73 (m, 4H) 4.37-4.52 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.71, 5.81 Hz, 1H) 2.69 (d, J=15.77 Hz, 1H) 2.26 (d, J=1.59 Hz, 3H) 1.18 (d, J=6.85 Hz, 3H).

Compound 086_E2: (4R*,9R)—N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 420. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.24-7.27 (m, 1H), 7.09-7.15 (m, 1H), 6.87-6.98 (m, 1H), 6.28-6.40 (m, 1H), 5.07-5.23 (m, 1H), 4.82-4.91 (m, 1H), 4.37-4.79 (m, 6H), 3.33 (s, 3H), 2.99-3.11 (m, 1H), 2.62-2.74 (m, 1H), 2.26 (d, J=1.71 Hz, 3H), 1.18 (d, J=6.85 Hz, 3H).

*Pure but unknown enantiomer.

Compound 087_E1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 431. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.78 (dd, J=5.46, 2.82 Hz, 1H) 7.58 (ddd, J=9.13, 4.55, 2.89 Hz, 1H) 7.09-7.18 (m, 1H) 6.62 (s, 1H) 5.08-5.19 (m, 1H) 4.84 (d, J=15.69 Hz, 1H) 4.57-4.73 (m, 4H) 4.38-4.54 (m, 2H) 3.33 (s, 3H) 3.04 (dd, J=15.94, 5.90 Hz, 1H) 2.71 (d, J=16.19 Hz, 1H) 1.19 (d, J=6.90 Hz, 3H).

Compound 087_E2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 431. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.74-7.81 (m, 1H), 7.59 (ddd, J=2.82, 4.49, 9.13 Hz, 1H), 7.14 (t, J=8.66 Hz, 1H), 6.67 (s, 1H), 5.13 (quin, J=6.40 Hz, 1H), 4.87 (d, J=15.69 Hz, 1H), 4.58-4.78 (m, 3H), 4.39-4.57 (m, 3H), 3.33 (s, 3H), 3.04 (dd, J=5.77, 15.94 Hz, 1H), 2.69 (d, J=15.94 Hz, 1H), 1.19 (d, J=7.03 Hz, 3H).

Compound 088_E1: (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 426. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.37 (ddd, J=2.8, 6.4, 12.0 Hz, 1H), 7.24 (td, J=2.4, 5.2 Hz, 1H), 6.64 (s, 1H), 5.14 (m, 1H), 4.84 (d, J=16.0 Hz, 1H), 4.54-4.59 (m, 2H), 4.39-4.50 (m, 3H), 3.32 (s, 3H), 3.04 (dd, J=8.0, 16.0 Hz, 1H), 2.69 (d, J=16.0 Hz, 1H), 1.18 (d, J=8.0 Hz, 3H).

Compound 088_E2: (4R*,9R)—N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 426. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.61 (m, 1H), 7.17-7.24 (m, 1H), 7.01-7.09 (m, 1H), 6.60 (s, 1H), 5.13 (quin, J=6.40 Hz, 1H), 4.86 (d, J=15.69 Hz, 1H), 4.57-4.75 (m, 3H), 4.52-4.56 (m, 1H), 4.37-4.48 (m, 2H), 3.25-3.38 (m, 3H), 2.96-3.10 (m, 1H), 2.67 (d, J=15.94 Hz, 1H), 1.17 (d, J=6.90 Hz, 3H).

*Pure but unknown enantiomer.

Compound 089_E1: (4S*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.29 (t, J=7.89 Hz, 1H), 6.90 (dd, J=7.95, 10.64 Hz, 1H), 6.52 (br d, J=2.81 Hz, 1H), 4.97-5.18 (m, 1H), 4.82 (d, J=15.77 Hz, 1H), 4.35-4.65 (m, 4H), 3.66-3.86 (m, 2H), 3.30 (s, 3H), 3.02 (dd, J=5.75, 15.89 Hz, 1H), 2.66 (d, J=15.89 Hz, 1H), 1.18 (d, J=6.85 Hz, 3H).

*Pure but unknown enantiomer.

Compound 089_E2: (4R*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.32 (t, J=7.89 Hz, 1H), 6.94 (dd, J=7.95, 10.64 Hz, 1H), 6.57 (br d, J=2.69 Hz, 1H), 5.10 (br t, J=6.42 Hz, 1H), 4.91 (d, J=15.65 Hz, 1H), 4.33-4.61 (m, 4H), 3.70-3.97 (m, 2H), 3.33 (s, 3H), 3.05 (dd, J=5.81, 15.83 Hz, 1H), 2.70 (d, J=15.77 Hz, 1H), 1.20 (d, J=6.97 Hz, 3H).

Compound 090_E1: (4S*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.19 (t, J=8.07 Hz, 1H), 6.95 (dd, J=8.50, 10.58 Hz, 1H), 6.54 (br s, 1H), 5.08 (br t, J=6.79 Hz, 1H), 4.85 (d, J=15.65 Hz, 1H), 4.41-4.67 (m, 4H), 3.68-3.94 (m, 2H), 3.34 (s, 2H), 2.97-3.12 (m, 1H), 2.70 (d, J=15.77 Hz, 1H), 1.21 (d, J=6.97 Hz, 3H).

Compound 090_E2: (4R*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.09-8.35 (m, 1H), 7.27 (s, 1H), 6.88-7.07 (m, 1H), 6.56 (br s, 1H), 5.11 (br d, J=6.27 Hz, 1H), 4.90 (br d, J=15.69 Hz, 1 H), 4.32-4.73 (m, 4H), 3.69-4.00 (m, 2H), 3.33 (s, 3H), 3.05 (br dd, J=5.14, 16.06 Hz, 1H), 2.70 (br d, J=16.06 Hz, 1H), 1.20 (br d, J=6.78 Hz, 3H).

Compound 091_E1: (4S*,9R)—N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.89 (dt, J=5.62, 8.93 Hz, 1H), 6.90-7.02 (m, 1H), 6.55 (br s, 1H), 5.09 (br t, J=6.60 Hz, 1H), 4.89 (d, J=15.89 Hz, 1H), 4.42-4.64 (m, 4H), 3.69-3.93 (m, 2H), 3.35 (s, 3H), 3.07 (dd, J=6.05, 15.71 Hz, 1H), 2.71 (d, J=15.77 Hz, 1H), 1.23 (d, J=6.97 Hz, 3H).

Compound 091_E2: (4R*,9R)—N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 8=7.89 (dt, J=5.56, 8.89 Hz, 1H), 6.90-7.03 (m, 1H), 6.57 (br s, 1H), 5.10 (quin, J=6.27 Hz, 1H), 4.94 (d, J=15.77 Hz, 1H), 4.37-4.63 (m, 4H), 3.75-3.97 (m, 2H), 3.35 (s, 3H), 3.07 (dd, J=5.87, 15.77 Hz, 1H), 2.71 (d, J=15.77 Hz, 1H), 1.22 (d, J=6.85 Hz, 3H).

Compound 092_E1: (4S*,9R)—N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.95 (dt, J=5.58, 8.94 Hz, 1H), 6.88-7.05 (m, 1H), 6.54 (br d, J=2.64 Hz, 1H), 5.09 (br t, J=6.53 Hz, 1H), 4.89 (d, J=15.94 Hz, 1H), 4.39-4.67 (m, 4H), 3.72-3.94 (m, 2H), 3.35 (s, 3H), 3.06 (dd, J=6.02, 15.81 Hz, 1H), 2.71 (d, J=15.81 Hz, 1H), 1.23 (d, J=6.90 Hz, 3H).

Compound 092_E2: (4R*,9R)—N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 502/500[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.95 (dt, J=5.69, 8.96 Hz, 1H), 6.88-7.03 (m, 1H), 6.60 (br s, 1H), 5.02-5.24 (m, 1H), 4.95 (d, J=15.65 Hz, 1H), 4.34-4.63 (m, 4H), 3.73-3.95 (m, 2H), 3.07 (dd, J=5.81, 15.96 Hz, 1H), 2.71 (d, J=16.02 Hz, 1H), 1.21 (d, 6.85 Hz, 3H).

Compound 093_D1: (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 1.50 g, 4.09 mmol, 1.00 eq) in DCM (4.00 mL) was added TEA (2.07 g, 20.47 mmol, 2.84 mL, 5.00 eq), and DMAP (50.01 mg, 409.38 μmol, 0.10 eq), followed by MsCl (1.41 g, 12.27 mmol, 949.68 μL 3.00 eq) at 0° C. The mixture was stirred at 20° C. for 1 hr. TLC (petroleum ether:ethyl acetate=0:1) showed the starting material consumed and one main spot was generated. The mixture combined with another batch (1.3 g scale) was extracted with DCM (30 mL*2) and H₂O (20 mL). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (petroleum ether:ethyl acetate: 30%˜50%) to get the title compound (1.50 g, 2.70 mmol, 66.01% yield) as a white solid.

Step 2, tert-butyl (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.10 g, 2.47 mmol, 1.00 eq) and Me₂NH (2.01 g, 24.70 mmol, 2.26 mL, 10.00 eq, HCl) in MeCN (60.00 mL) was added K₂CO₃ (4.44 g, 32.11 mmol, 13.00 eq). The mixture was heated to 80° C. for 16 hr. TLC (petroleum ether:ethyl acetate=0:1) showed the starting material consumed and one main spot was detected. The mixture was extracted with ethyl acetate (100 mL*2) and H₂O (50 mL). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate:80%˜100%) to get the title compound (800.00 mg, 1.97 mmol, 79.76% yield, 96.7% purity) as yellow solid and (200.00 mg, 72% purity) as yellow oil.

The diastereomeric mixture (1.0 g) was separated via SFC to get both diasteromers (360 mg) and (360 mg). SFC separation method: Instrument: SFC Thar_80; Column: IC-10 um; Mobile phase: A for CO₂ and B for MeOH (0.1% Ammonia); Isocratic: B 25%; Flow rate: 55 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

Step 3. (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (360.00 mg, 914.91 μmol, 1.00 eq) in DCM (4.00 mL) was added TFA (6.16 g, 54.03 mmol, 4.00 mL, 59.05 eq). The mixture was stirred at 20° C. for 1 hr. TLC (DCM:MeOH=10:1) showed the starting material was consumed. The mixture was concentrated in vacuum to get the title compound (380.00 mg, crude, TFA) as yellow oil.

Step 4. (9R)—N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino)methyl]-2,9-dim ethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of (9R)-4-[(dimethylamino)methyl]-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (44.00 mg, 108.00 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (28.69 mg, 108.00 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (54.64 mg, 540.00 μmol, 74.85 μL 5.00 eq). The mixture was heated to 20° C. for 16 hr. LCMS showed one main peak with desired Ms. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get the title compound (38.00 mg, 81.65 μmol, 75.60% yield, 99.9% purity) as a white solid. LCMS (M+1): 465. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.21 (s, 1H), 7.61 (dd, J=2.64, 6.53 Hz, 1H), 7.19-7.26 (m, 1H), 7.03-7.12 (m, 1H), 6.61 (s, 1H), 5.08-5.19 (m, 1H), 4.75-4.89 (m, 2H), 4.62 (dd, J=5.90, 14.68 Hz, 1H), 4.50 (d, J=15.69 Hz, 1H), 4.37 (dd, J=4.77, 14.56 Hz, 1H), 3.34 (s, 3H), 3.05 (br dd, J=5.96, 15.87 Hz, 2H), 2.66-2.77 (m, 3H), 2.48 (s, 6H).

Compounds 094, 095, 096, 097, 098, 099, and 100 were prepared in an analogous method to Compound 093_D1.

Compound 093_D2: (4R*,9R)—N-(3-chloro-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 465. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.13 (s, 1H), 7.61 (dd, J=2.64, 6.53 Hz, 1H), 7.17-7.25 (m, 1H), 7.03-7.12 (m, 1H), 6.56 (s, 1H), 5.16 (quin, J=6.68 Hz, 1H), 4.87 (d, J=15.56 Hz, 1H), 4.56-4.75 (m, 2H), 4.47 (d, J=15.56 Hz, 1H), 4.33 (dd, J=5.90, 14.43 Hz, 1H), 3.34 (s, 3H), 3.05 (dd, J=5.90, 15.81 Hz, 1H), 2.58-2.81 (m, 4H), 2.43 (s, 6H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 094_D1: (4S*,9R)—N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 509/511. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.22 (brs, 1H), 7.73 (dd, J=2.64, 6.02 Hz, 1H), 7.30 (dd, J=2.70, 4.20 Hz, 1H), 7.27 (d, J=2.64 Hz, 1H), 7.06 (t, J=8.53 Hz, 1H), 6.59 (br s, 1H), 5.14 (quin, J=6.49 Hz, 1H), 4.71-4.90 (m, 2H), 4.61 (dd, J=5.90, 14.56 Hz, 1H), 4.50 (d, J=15.56 Hz, 1H), 4.37 (dd, J=4.83, 14.62 Hz, 1H), 3.34 (s, 3H), 3.05 (dd, J=5.77, 15.81 Hz, 1H), 2.65-2.77 (m, 3H), 2.47 (s, 6H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 094_D2: (4R*,9R)—N-(3-bromo-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 509/511. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.12 (s, 1H), 7.75 (dd, J=2.64, 6.02 Hz, 1H), 7.30 (dd, J=2.76, 4.14 Hz, 1H), 7.02-7.10 (m, 1H), 6.60 (s, 1H), 5.16 (quin, J=6.27 Hz, 1H), 4.75-4.93 (m, 2H), 4.62 (dd, J=5.90, 14.56 Hz, 1H), 4.45 (d, J=15.56 Hz, 1H), 4.35 (dd, J=5.33, 14.62 Hz, 1H), 3.35 (s, 3H), 3.05 (dd, J=5.71, 15.87 Hz, 1H), 2.67-2.83 (m, 3H), 2.53 (s, 5H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 096_D1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 456. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.18 (s, 1H), 7.80 (dd, J=2.76, 5.40 Hz, 1H), 7.62 (ddd, J=2.76, 4.58, 9.10 Hz, 1H), 7.09-7.20 (m, 1H), 6.76 (s, 1H), 5.14 (quin, J=6.40 Hz, 1H), 4.79-4.90 (m, 2H), 4.63 (dd, J=5.90, 14.68 Hz, 1H), 4.51 (d, J=15.69 Hz, 1H), 4.38 (dd, J=4.71, 14.62 Hz, 1H), 3.35 (s, 3H), 3.05 (dd, J=5.90, 15.94 Hz, 1H), 2.66-2.82 (m, 3H), 2.52 (s, 6H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 096_D2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 456. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.10 (s, 1H), 7.81 (dd, J=2.82, 5.46 Hz, 1H), 7.62 (ddd, J=2.76, 4.58, 9.10 Hz, 1H), 7.15 (t, J=8.72 Hz, 1H), 6.81 (s, 1H), 5.16 (quin, J=6.40 Hz, 1H), 4.78-4.96 (m, 2H), 4.62 (dd, J=6.02, 14.68 Hz, 1H), 4.31-4.48 (m, 2H), 3.35 (s, 3H), 3.05 (dd, J=5.77, 16.06 Hz, 1H), 2.87 (br d, J=6.15 Hz, 2H), 2.70 (d, J=16.06 Hz, 1H), 2.58 (s, 6H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 095_D1: (4S*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 510/512. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.14-8.18 (m, 1H) 8.07 (d, J=5.62 Hz, 1H) 6.97 (br s, 1H) 5.05 (br t, J=6.54 Hz, 1H) 4.89 (br d, J=16.02 Hz, 1H) 4.81 (br d, J=6.36 Hz, 1H) 4.51-4.64 (m, 2H) 4.38 (dd, J=14.61, 4.34 Hz, 1H) 3.33 (s, 3H) 3.06 (dd, J=15.89, 5.75 Hz, 1H) 2.69-2.78 (m, 3H) 2.49 (s, 6H) 1.24 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 095_D2: (4R*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 510/512. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.13-8.17 (m, 1H) 8.06 (d, J=5.52 Hz, 1H) 7.02 (br d, J=3.89 Hz, 1H) 5.07 (br t, J=6.40 Hz, 1H) 4.93 (d, J=15.81 Hz, 1H) 4.48-4.68 (m, 3H) 4.29 (dd, J=14.24, 6.09 Hz, 1H) 3.32 (s, 3H) 3.05 (dd, J=15.94, 5.90 Hz, 1H) 2.68-2.76 (m, 2H) 2.60 (dd, J=13.24, 5.08 Hz, 1H) 2.40 (s, 6H) 1.23 (d, J=6.90 Hz, 3H).

Compound 097_D1: (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 445. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.23-7.27 (m, 1H) 7.08-7.14 (m, 1H) 6.92 (t, J=8.97 Hz, 1H) 6.48 (s, 1H) 5.12 (m, J=6.49 Hz, 1H) 4.79-4.92 (m, 2H) 4.61 (dd, J=14.68, 6.02 Hz, 1H) 4.48 (d, J=15.69 Hz, 1H) 4.37 (dd, J=14.68, 4.27 Hz, 1H) 3.33 (s, 3H) 3.03 (dd, J=15.87, 5.96 Hz, 1H) 2.83-2.91 (m, 1H) 2.73-2.81 (m, 1H) 2.67 (d, J=15.81 Hz, 1H) 2.51-2.56 (m, 6H) 2.25 (d, J=1.76 Hz, 3H) 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 097_D2: (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 445. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.23-7.27 (m, 1H) 7.11 (dt, J=7.87, 3.91 Hz, 1H) 6.92 (t, J=8.97 Hz, 1H) 6.56 (s, 1H) 5.13 (m, J=6.37 Hz, 1H) 4.86-4.98 (m, 2H) 4.62 (dd, J=14.81, 6.02 Hz, 1H) 4.32-4.43 (m, 2H) 3.33 (s, 3H) 2.98-3.09 (m, 2H) 2.92 (dd, J=13.55, 8.41 Hz, 1H) 2.62-2.70 (m, 7H) 2.24 (d, J=1.76 Hz, 3H) 1.17 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compound 098_D1: (4S*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 499. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=6.15, 2.76 Hz, 1H) 7.60 (dt, J=8.56, 3.62 Hz, 1H) 7.12 (t, J=9.41 Hz, 1H) 6.82 (s, 1H) 5.14 (m, J=6.46 Hz, 1H) 4.86 (d, J=15.69 Hz, 1H) 4.76 (m, J=5.65 Hz, 1H) 4.60 (dd, J=14.68, 5.90 Hz, 1H) 4.49 (d, J=15.56 Hz, 1H) 4.34 (dd, J=14.62, 5.08 Hz, 1H) 3.32 (s, 3H) 3.04 (dd, J=15.94, 5.77 Hz, 1H) 2.65-2.71 (m, 3H) 2.44 (s, 6H) 1.18 (d, J=6.90 Hz, 3H)

Compound 098_D2: (4R*,9R)-4-((dimethylamino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 499. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=6.05, 2.63 Hz, 1H) 7.57-7.64 (m, 1H) 7.12 (t, J=9.41 Hz, 1H) 6.85 (s, 1H) 5.15 (m, J=6.39 Hz, 1H) 4.85-4.96 (m, 2H) 4.61 (dd, J=14.67, 5.99 Hz, 1H) 4.32-4.46 (m, 2H) 3.33 (s, 3H) 3.03 (dd, J=15.96, 5.81 Hz, 1H) 2.83-2.96 (m, 2H) 2.67 (d, J=15.89 Hz, 1H) 2.60 (s, 6H) 1.18 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 099_D1: (4S*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 483/485. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.16-8.22 (m, 1H), 8.19 (t, J=7.72 Hz, 1H), 8.16 (s, 1H), 8.15-8.16 (m, 1H), 6.95 (dd, J=8.41, 10.54 Hz, 1H), 6.54 (d, J=3.26 Hz, 1H), 5.08 (s, 1H), 4.85 (d, J=15.69 Hz, 1H), 4.77 (dd, J=4.96, 5.96 Hz, 1H), 4.49-4.62 (m, 2H), 4.36 (dd, J=4.64, 14.56 Hz, 1H), 3.33 (s, 3H), 3.05 (dd, J=5.90, 15.81 Hz, 1H), 2.65-2.75 (m, 3H), 2.45 (s, 6H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 099_D2: (4R*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 483/485. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.20 (t, J=7.98 Hz, 1H), 8.17-8.23 (m, 1H), 8.16 (s, 1H), 8.15-8.17 (m, 1H), 6.97 (dd, J=8.41, 10.54 Hz, 1H), 6.57 (br d, J=3.14 Hz, 1H), 5.11 (s, 1H), 4.91 (d, J=15.69 Hz, 1H), 4.78 (s, 1H), 4.62 (dd, J=5.96, 14.62 Hz, 1H), 4.49 (d, J=15.56 Hz, 1H), 4.33 (dd, J=5.71, 14.62 Hz, 1H), 3.34 (s, 3H), 3.05 (d, J=5.77 Hz, 1H), 2.63-2.86 (m, 3H), 2.51 (s, 6H), 1.22 (d, J=6.90 Hz, 3H).

Compound 100_D1: (4S*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 527/529. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.33 (dd, J=7.59, 8.22 Hz, 1H), 8.22 (s, 1H), 7.29 (s, 1H), 6.95 (dd, J=7.91, 10.67 Hz, 1H), 6.57 (br d, J=3.01 Hz, 1H), 5.09 (br t, J=6.46 Hz, 1H), 4.79-4.91 (m, 2H), 4.49-4.65 (m, 2H), 4.38 (dd, J=4.45, 14.62 Hz, 1H), 3.34 (s, 3H), 3.02-3.10 (m, 1H), 2.68-2.83 (m, 3H), 2.50 (s, 6H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 100_D2: (4R*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((dimethylamino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 527/529. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.34 (dd, J=7.53, 8.28 Hz, 1H), 8.17 (s, 1H), 6.95 (dd, J=7.91, 10.67 Hz, 1H), 6.57 (d, J=3.01 Hz, 1H), 5.11 (s, 1H), 4.91 (d, J=15.69 Hz, 1H), 4.74 (s, 1H), 4.62 (dd, J=5.90, 14.56 Hz, 1H), 4.49 (d, J=15.69 Hz, 1H), 4.33 (dd, J=5.96, 14.49 Hz, 1H), 3.34 (s, 3H), 3.02-3.10 (m, 1H), 2.62-2.83 (m, 3H), 2.55 (br s, 7H), 2.47 (s, 6H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 101: N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 100.00 mg, 283.78 μmol, 1.00 eq) in DMF (2.00 mL) was added NaH (22.70 mg, 567.56 μmol, 22.70 μL 60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N₂. And then a solution of iodoethane (66.39 mg, 425.67 μmol, 34.04 μL 1.50 eq) in DMF (1.00 mL) was added into the mixture. The mixture was stirred at 15° C. for 1 h. TLC (Petroleum ether:Ethyl acetate=1:5) showed that the starting material was consumed completely and one main new spot formed. LCMS indicated that MS of desired product was detected. The mixture was quenched with 1 mL of water and extracted with EtOAc (10 mL*3). The organic layers was combined and dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue. The residue was purified by prep-TLC (Petroleum ether:Ethyl acetate=1:5) to obtain the title compound (105.00 mg, crude) as off-white oil. LCMS [M+1]: 381.

Step 2. Preparation of 4-(ethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (50.00 mg, 131.43 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 102.76 eq) with stirring at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:5) showed that Reactant 2 was consumed completely and one main new spot formed. The mixture was directly evaporated to give the residue. The residue was not purified and directly used in the next step. The title compound (60.00 mg, crude, TFA) was obtained as a yellow oil.

Step 3. N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 4-(ethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-1-one (60.00 mg, 152.15 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was TEA (46.19 mg, 456.45 μmol, 63.27 μL 3.00 eq) with stirring at 15° C., and then the resulting mixture was stirred at 30° C. for 1 h. TLC showed the starting material was consumed completely and LCMS indicated that MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (28.00 mg, 61.78 μmol, 40.60% yield, 99.7% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.8, 6.4 Hz, 1H), 7.20 (m, 1H), 7.03-7.10 (m, 1 H), 6.55 (s, 1H), 4.70 (s, 2H), 4.51-4.64 (m, 2H), 4.35-4.46 (m, 1H), 3.79-3.94 (m, 2H), 3.51-3.67 (m, 4H), 3.31 (s, 3H), 2.86 (t, J=5.6 Hz, 2H), 1.24 (t, J=6.8 Hz, 3H). LCMS[M+1]: 452.

Compound 102: 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 4-(allyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.57 μmol, 1.00 eq) in DMF (2.00 mL) was NaH (45.41 mg, 1.14 mmol, 22.70 μL 60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N₂. And then 3-bromoprop-1-ene (103.00 mg, 851.35 μmol, 1.50 eq) was added into the mixture. The mixture was stirred at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:5) showed that the starting material was consumed completely and one main new spot formed. LCMS indicated that MS of desired product was detected. The mixture was quenched with 1 mL of water and extracted with ethyl acetate (10 mL*3). The organic layers was combined and dried over anhydrous Na₂SO₄, filtered and concentrated to obtain the title compound (160.00 mg, 407.70 μmol, 71.83% yield) as off-white oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=5.96-5.84 (m, 1H), 5.33-5.20 (m, 2H), 4.63 (brs, 2H), 4.60-4.48 (m, 2H), 4.40-4.31 (m, 1H), 4.04 (d, J=5.6 Hz, 2H), 3.70 (d, J=5.2 Hz, 2H), 3.64 (dd, J=6.0, 12.0 Hz, 1H), 3.57-3.50 (m, 1H), 3.27 (s, 3H), 2.81-2.72 (m, 2H), 1.47 (s, 9H). LCMS [M+1]: 393.

Step 2. Preparation of 4-(allyloxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-(allyloxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (30.00 mg, 76.44 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL 88.35 eq) with stirring at 15° C. for 1 h. TLC indicated that the starting material was consumed completely and one main spot formed. The mixture was directly evaporated to obtain the title compound (50.00 mg, crude, TFA) as a yellow oil and directly used in the next step.

Step 3, 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 4-(allyloxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (31.00 mg, 76.29 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (22.29 mg, 83.92 μmol, 1.10 eq) in DCM (2.00 mL) was added TEA (73.00 mg, 721.70 μmol, 100.00 μL 9.46 eq) with stirring at 30° C. for 1 h. LCMS indicated that the starting material was consumed completely and MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (25.70 mg, 55.01 μmol, 72.11% yield, 99.3% purity) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.51-7.63 (m, 1H), 7.16-7.25 (m, 1H), 6.98-7.08 (m, 1H), 6.61-6.79 (m, 1H), 5.83-5.98 (m, 1H), 5.19-5.34 (m, 2H), 4.69 (s, 2H), 4.48-4.64 (m, 2H), 4.31-4.44 (m, 1H), 4.00-4.11 (m, 2H), 3.76-3.94 (m, 2H), 3.52-3.69 (m, 2H), 3.29 (s, 3H), 2.85 (t, J=5.60 Hz, 2H). LCMS[M+1]: 464.

Compound 103: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 100.00 mg, 283.78 μmol, 1.00 eq) in DMF (2.00 mL) was added NaH (45.41 mg, 1.14 mmol, 22.70 μL 60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N₂. And then 1-bromopropane (52.35 mg, 425.68 μmol, 38.78 μL 1.50 eq) was added into the mixture. The mixture was stirred at 15° C. for 1 h. TLC (petroleum ether:ethyl acetate=1:5) showed that the starting material, was consumed completely and one main new spot formed. LCMS indicated that MS of desired product was detected. The mixture was quenched with 1 mL of water and extracted with ethyl acetate (10 mL*3). The organic layers was combined and dried over anhydrous Na₂SO₄, filtered and concentrated to obtain the title compound (60.00 mg, 152.11 μmol, 53.60% yield) as off-white oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.62 (brs, 2H), 4.46-4.58 (m, 2H), 4.29-4.39 (m, 1H), 3.69 (d, J=4.77 Hz, 2H), 3.58-3.64 (m, 1H), 3.47-3.55 (m, 1H), 3.39-3.47 (m, 2H), 3.26 (s, 3H), 2.74 (t, J=5.14 Hz, 2H), 1.55-1.64 (m, 2H), 1.46 (s, 9H), 0.86-0.97 (m, 3H). LCMS[M+1]: 395.

Step 2. 2-methyl-4-(propoxymethyl)-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (60.00 mg, 152.11 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 88.79 eq) with stirring at 15° C. for 1 h. TLC indicated that the starting material was consumed completely and one main spot formed. The mixture was directly evaporated to obtain the title compound (70.00 mg, crude, TFA) as yellow oil and directly used in the next step. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.47-4.71 (m, 5H), 3.57-3.73 (m, 4H), 3.42-3.54 (m, 2H), 3.33 (s, 3H), 3.17 (t, J=6.0 Hz, 2H), 1.59-1.69 (m, 2H), 0.89-0.98 (m, 3H).

Step 3, N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(propoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 2-methyl-4-(propoxymethyl)-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (70.00 mg, 171.41 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (45.54 mg, 171.41 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (164.09 mg, 1.62 mmol, 224.78 μL 9.46 eq) with stirring at 30° C. for 1 h. LCMS indicated that the starting material was consumed completely and MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (19.00 mg, 40.46 μmol, 23.60% yield, 99.2% purity) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.16-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.48 (s, 1H), 4.70 (s, 2H), 4.51-4.63 (m, 2H), 4.37-4.43 (m, 1H), 3.80-3.93 (m, 2H), 3.62-3.68 (m, 1H), 3.52-3.59 (m, 1H), 3.44-3.51 (m, 2H), 3.31 (s, 3H), 2.86 (t, J=5.81 Hz, 2H), 1.61-1.68 (m, 2H), 0.95 (t, J=7.40 Hz, 3H). LCMS[M+1]: 466.

Compound 104: N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of tert-butyl4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1,500.00 mg, 1.42 mmol, 1.00 eq) in DMF (5.00 mL) was added NaH (113.51 mg, 2.84 mmol, 22.70 μL 60% purity, 2.00 eq) with stirring at −10° C. for 0.5 h under N₂. Then bromomethylcyclopropane (287.33 mg, 2.13 mmol, 203.78 μL 1.50 eq) was added into the mixture. The mixture was stirred at 0° C. for 1 h. TLC showed that the starting material was consumed completely and one main new spot formed. The mixture was quenched with 1 mL of water and extracted with EtOAc (10 mL*3). The organic layers was combined and dried over anhydrous Na₂SO₄, filtered and concentrated to give a residue. The residue was purified by prep-TLC to obtain the title compound (290.00 mg, 713.46 μmol, 50.24% yield) as yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=4.62 (brs, 2H), 4.46-4.59 (m, 2H), 4.28-4.38 (m, 1H), 3.66 (dt, 5.50, 11.07 Hz, 3H), 3.53 (dd, J=5.26, 10.15 Hz, 1H), 3.33 (dd, J=2.32, 6.85 Hz, 2H), 3.27 (s, 3H), 2.74 (br s, 2H), 1.39-1.53 (m, 9H), 0.99-1.10 (m, 1H), 0.49-0.59 (m, 2H), 0.15-0.24 (m, 2H).

Step 2. Preparation of 4-(cyclopropylmethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (80.00 mg, 196.82 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (3.99 g, 34.95 mmol, 2.59 mL, 177.60 eq) with stirring at 15° C. for 1 h. TLC showed that the starting material was consumed completely. The mixture was directly evaporated to get the title compound (85.00 mg, crude, TFA) as a yellow oil and directly used in the next step.

Step 3. N-(3-chloro-4-fluoro-phenyl)-4-(cyclopropylmethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 4-(cyclopropylmethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (83.00 mg, 197.44 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (57.70 mg, 217.18 μmol, 1.10 eq) in DCM (2.00 mL) was added TEA (201.99 mg, 2.00 mmol, 276.70 μL 10.11 eq) with stirring at 30° C. for 1 h. LCMS indicated that reactant was consumed completely and MS of desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (48.60 mg, 100.67 μmol, 50.99% yield, 99% purity) as white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.54 (dd, J=2.63, 6.54 Hz, 1H), 7.14-7.23 (m, 1H), 7.03 (t, J=8.80 Hz, 1H), 6.71 (s, 1H), 4.69 (s, 2H), 4.51-4.63 (m, 2H), 4.34-4.44 (m, 1H), 3.75-3.91 (m, 2H), 3.52-3.72 (m, 2H), 3.33-3.39 (m, 2H), 3.29 (s, 3H), 2.84 (t, J=5.75 Hz, 2H), 1.01-1.12 (m, 1H), 0.52-0.61 (m, 2H), 0.19-0.26 (m, 2H). LCMS (M+1): 478.

Compound 105: N-(3-chloro-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.57 μmol, 1.00 eq) in DMF (2.00 mL) was added NaH (68.11 mg, 1.70 mmol, 22.70 μL 60% purity, 3.00 eq) with stirring at −10° C. for 0.5 h under N₂. Then the resulting DMF solution of 2,2-difluoroethyl trifluoromethanesulfonate (Intermediate 19, 5.68 mmol, 1.00 mL, 10.00 eq) was added into the mixture. The mixture was stirred at 0° C. for 2 h. TLC (PE:EtOAc=1:5) showed that the first reactant was consumed completely and some new spots formed. LCMS indicated that the desired product was detected. The mixture was poured into 10 mL of ice water and extracted with Ethyl acetate (10 mL*3). The organic layers was combined and dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue. The residue was purified by prep-TLC to obtain the title compound (100.00 mg, 240.14 μmol, 42.31% yield) as yellow oil. ¹H NMR (400 MHz, CHLOROFORM-d) δ=5.69-6.04 (m, 1H), 4.45-4.63 (m, 4H), 4.27-4.40 (m, 1H), 3.59-3.79 (m, 6H), 3.24 (s, 3H), 2.64-2.78 (m, 2H), 1.45 (s, 9H).

Step 3. Preparation of 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (100.00 mg, 240.14 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 56.24 eq) with stirring at 15° C. for 1 h. TLC showed that reactant was consumed completely and one new spot formed. The mixture was directly evaporated to get the title compound (110.00 mg, crude, TFA) as yellow oil and directly used in the next step.

Step 4. N-(3-chloro-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (103.00 mg, 239.35 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (193.76 mg, 1.91 mmol, 265.42 μL 8.00 eq) with stirring at 30° C. for 1 h. LCMS indicated that reactant was consumed completely and the desired product was detected. The mixture was evaporated to get the residue. The residue was purified by prep-HPLC (FA) to obtain the title compound (61.00 mg, 124.29 μmol, 51.93% yield, 99.4% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.54 (dd, J=2.70, 6.59 Hz, 1H), 7.19 (ddd, J=2.70, 4.05, 8.94 Hz, 1H), 6.99-7.08 (m, 1H), 6.73 (s, 1H), 5.72-6.06 (m, 1H), 4.69 (s, 2H), 4.51-4.64 (m, 2H), 4.33-4.43 (m, 1H), 3.81-3.90 (m, 2H), 3.66-3.80 (m, 4H), 3.24-3.35 (m, 3H), 2.77-2.91 (m, 2H). LCMS (M+1): 488.

Compound 106: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. tert-butyl 2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-bpyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq) in DMF (2.00 mL) was added NaH (170.27 mg, 4.26 mmol, 22.70 μL 60% purity, 3.00 eq) at −10° C. The mixture was stirred for 0.5 h under N₂. Then a DMF solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (Intermediate 20, 14.19 mmol, 1 mL, 10.00 eq) was added to the mixture. The mixture was stirred at 0° C. for 5 h. LCMS indicated that the MS of desired product was detected. The mixture was poured into 10 mL of ice water and extracted with Ethyl acetate (10 mL*3). The organic layers were combined and dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue. The residue was purified by prep-TLC to obtain the title compound (160.00 mg, crude) as yellow oil. LCMS: 435 (M+1).

Step 3. Preparation of 2-methyl-4-(2,2,2-trifluoroethoxy methyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (80.00 mg, 184.16 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 73.34 eq) with stirring at 15° C. for 1 h. TLC showed that reactant was consumed completely and one new spot formed. The mixture was directly evaporated to get the title compound (85.00 mg, crude, TFA) as yellow oil.

Step 4. Preparation of Compound 106: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 2-methyl-4-(2,2,2-trifluoroethoxymethyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (30.00 mg, 66.92 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (17.78 mg, 66.92 μmol, 1.00 eq) in DCM (2.00 mL) was added TEA (54.17 mg, 535.33 μmol, 74.21 μL 8.00 eq) with stirring at 30° C. for 1 h. LCMS indicated that reactant was consumed completely and the desired product was detected. The mixture was evaporated in vacuo. The residue was purified by prep-HPLC (FA) to obtain the title compound (23.00 mg, 44.33 μmol, 33.12% yield, 97.5% purity) as a white solid. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.58 (dd, J=2.51, 6.65 Hz, 1H), 7.23-7.36 (m, 1H), 7.06-7.19 (m, 1H), 4.65-4.75 (m, 1H), 4.59 (br dd, J=5.71, 14.49 Hz, 1H), 4.37 (dd, J=6.90, 14.56 Hz, 1H), 4.02 (q, J=8.87 Hz, 1H), 3.75-3.91 (m, 1H), 3.28 (s, 1H), 2.82 (brt, J=5.58 Hz, 1H). LCMS: 506 (M+1).

Compound 107: N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-2-(trideuteriomethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of 4-(hydroxymethyl)-2-(trideuteriomethyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl 4-(hydroxymethyl)-2-(methyl-d3)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 21, 40.00 mg, 112.55 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 120.00 eq), and then the mixture was stirred at 10° C. for 1 hour. TLC showed the starting material was consumed completely and a new spot appeared. The mixture was concentrated in vacuum to give the title compound (41.57 mg, 112.56 μmol, 100.00% yield, TFA) as a yellow oil.

Step 2. N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1-oxo-2-(trideuteriomethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of 4-(hydroxymethyl)-2-(trideuteriomethyl)-4,5,8,9,10,11-hexahydropyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (41.57 mg, 112.56 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (32.89 mg, 123.82 μmol, 1.10 eq), TEA (22.78 mg, 225.12 μmol, 31.21 μL 2.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 10° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely and desired product was major. The mixture was poured into water (5 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (3 mL*3). The combined organic phase was washed with brine (5 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to give the title compound (21.00 mg, 48.21 μmol, 42.83% yield, 98% purity) as a white solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.59 (m, 1H) 7.16-7.22 (m, 1H) 7.06 (t, J=8.78 Hz, 1H) 6.51 (s, 1H) 4.70 (s, 2H) 4.51-4.62 (m, 2H) 4.34-4.47 (m, 1H) 3.74-3.93 (m, 4H) 2.86 (s, 2H) 1.87-2.07 (m, 1H). LCMS: 427 [M+1].

Compound 108_D1: (4S*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 108_D1 was prepared in an analogous manner to Compound 121.

LC-MS: 564/566 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.34 (t, J=7.89 Hz, 1H), 6.94 (dd, J=7.95, 10.64 Hz, 1H), 6.53 (br s, 1H), 5.68-6.13 (m, 1H), 5.09 (brt, J=6.17 Hz, 1H), 4.86 (d, J=15.77 Hz, 1H), 4.35-4.71 (m, 4H), 3.61-3.84 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.69, 15.71 Hz, 1H), 2.70 (d, J=15.89 Hz, 1H), 1.21 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 108_D2: (4R*,9R)—N-(5-bromo-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 108_D1 was prepared in an analogous manner to Compound 121.

LCMS (M+1): 564/566. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.31-8.37 (m, 1H), 6.94 (dd, J=7.91, 10.67 Hz, 1H), 6.53 (br s, 1H), 5.75-6.06 (m, 1H), 5.10 (br t, J=6.09 Hz, 1H), 4.88 (d, J=15.69 Hz, 1H), 4.37-4.64 (m, 4H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.46, 16.00 Hz, 1H), 2.71 (d, J=15.81 Hz, 1H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 109: (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 11. 9-ethyl-(hydroxymethyl)-1-methyl-4,5,8,9,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 23, 50.00 mg, 131.43 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 102.76 eq). The reaction mixture was stirred at 25° C. for 30 minutes. TLC indicated the starting material consumed completely, and one major new spot with larger polarity was detected. The reaction mixture was concentrated on a rotary evaporator to give the title compound (50.00 mg, crude, TFA) as yellow oil, used in next step directly.

Step 2. (4S*,9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a mixture of 9-ethyl-4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (50.00 mg, 126.79 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added TEA (51.32 mg, 507.16 μmol, 70.30 μL 4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (33.68 mg, 126.79 μmol, 1.00 eq), and the reaction mixture was stirred at 25° C. for 16 hours. LCMS showed one main peak with desired MS was detected. The mixture was extracted with DCM (50 mL) and water (30 mL*2), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(FA) to give the title compound (46.00 mg, 99.76 μmol, 78.68% yield, 98% purity) as white solid, which was separated by SFC, followed by prep-HPLC to get both diastereomers (109_D1: 20 mg and 109_D2: 20 mg).

SFC separation condition: Instrument: SFC 80; Column: AD-5 um; Mobile phase: A for CO₂ and B for IPA (0.1% NH₃H₂O); Gradient: B 30%; Flow rate: 60 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm. 1H NMR (400 MHz, CHLOROFORM-d) 8=7.59 (dd, J=2.70, 6.46 Hz, 1H), 7.16-7.23 (m, 1H), 7.03-7.10 (m, 1H), 6.50 (s, 1H), 4.81-4.89 (m, 2H), 4.51-4.63 (m, 2H), 4.40-4.48 (m, 2H), 3.72-3.89 (m, 2H), 3.33 (s, 3H), 3.00 (dd, J=5.77, 15.94 Hz, 1H), 2.77 (d, J=16.19 Hz, 1H), 1.95 (br s, 1H), 1.40-1.54 (m, 2H), 0.94 (t, J=7.40 Hz, 3H). LCMS: 452/454 [M+1]

* pure but unknown stereochemistry

Compound 109_D2: (4S*,9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.64, 6.53 Hz, 1H), 7.18-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.58 (s, 1H), 4.84-4.93 (m, 2H), 4.52-4.60 (m, 2H), 4.35-4.43 (m, 2H), 3.75-3.92 (m, 2H), 3.33 (s, 3H), 3.00 (dd, J=6.02, 16.06 Hz, 1H), 2.77 (d, J=15.81 Hz, 1H), 1.92-2.08 (m, 1H), 1.42-1.55 (m, 2H), 0.94 (t, J=7.34 Hz, 3H).

LCMS: 452/454 [M+1]

* pure but unknown stereochemistry

Compounds 109_D3/D4 were prepared through the similar procedure of 109_D1/D2.

SFC separation condition: Instrument: SFC 80; Column: OJ-5 um; Mobile phase: A for CO₂ and B for EtOH (0.1% NH₃H₂O); Gradient: B 20%; Flow rate: 50 mL/min; Back pressure: 100 bar; Column temperature: 35° C.; Wavelength: 220 nm.

109_D3: (4R*,9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.64, 6.53 Hz, 1H), 7.18-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.52 (s, 1H), 4.84-4.92 (m, 2H), 4.52-4.59 (m, 2H), 4.36-4.43 (m, 2H), 3.86-3.92 (m, 1H), 3.76-3.82 (m, 1H), 3.33 (s, 3H), 3.00 (dd, J=5.83, 16.00 Hz, 1H), 2.77 (d, J=15.94 Hz, 1H), 1.83-2.04 (m, 1H), 1.41-1.55 (m, 2H), 0.94 (t, J=7.40 Hz, 3H)

LCMS: 452 [M+1].

* pure but unknown stereochemistry

109_D4: (4R*,9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

1H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.64, 6.53 Hz, 1H), 7.20 (ddd, J=2.70, 4.05, 8.94 Hz, 1H), 7.03-7.09 (m, 1H), 6.55 (br s, 1H), 4.84 (br d, J=15.69 Hz, 2H), 4.51-4.62 (m, 2H), 4.39-4.46 (m, 2H), 3.81-3.88 (m, 1H), 3.72-3.78 (m, 1H), 3.33 (s, 3H), 2.99 (dd, J=5.83, 16.00 Hz, 1H), 2.77 (d, J=15.94 Hz, 1H), 1.87-2.19 (m, 1H), 1.42-1.56 (m, 2H), 0.94 (t, J=7.40 Hz, 3H)

LCMS: 452 [M+1].

* pure but unknown stereochemistry

Compound 110_D1: (4S*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. (9R)—N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide

A solution of tert-butyl (9R)-2,9-dimethyl-4-(methylcarbamoyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 25, 165.00 mg, 419.38 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 32.21 eq), and then the mixture was stirred at 30° C. for 0.5 hour. TLC showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum to give the title compound (170.00 mg, 417.34 μmol, 99.51% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. (9R)-N10-(3-chloro-2,4-difluoro-phenyl)-N4,2,9-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

A mixture of (9R)—N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (56.00 mg, 137.48 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-2,4-difluoro-phenyl)carbamate (46.80 mg, 164.97 μmol, 1.20 eq), TEA (27.82 mg, 274.95 μmol, 38.11 μL 2.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely and desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (40.00 mg, 80.35 μmol, 58.45% yield, 97% purity) as a white solid. LCMS: 483/484[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.84-7.93 (m, 1H), 6.92-7.00 (m, 1H), 6.49-6.57 (m, 1H), 6.01-6.10 (m, 1H), 4.95-5.05 (m, 2H), 4.87-4.94 (m, 2H), 4.64-4.71 (m, 1H), 4.55 (s, 1H), 3.35 (s, 3H), 3.00-3.07 (m, 1H), 2.85 (d, J=4.89 Hz, 3H), 2.68-2.75 (m, 1H), 1.22 (d, J=6.90 Hz, 2H), 1.18-1.26 (m, 1H).

* pure but unknown stereochemistry

Compound 110_D2: (4R*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 110_D2 was prepared in an analogous manner to 110_D1 using the opposite enantiomer of Intermediate 25.

LCMS: 483/484[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.81-7.96 (m, 1H), 6.96 (br d, J=1.10 Hz, 1H), 6.49-6.61 (m, 1H), 6.07-6.22 (m, 1H), 5.02-5.11 (m, 1H), 4.84-5.00 (m, 3H), 4.75 (s, 1H), 4.48 (s, 1H), 3.35 (s, 3H), 3.00-3.10 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.72 (d, J=15.89 Hz, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compounds 156, 111, and 112 were prepared in an analogous manner to Compound 110.

Compound 111_D1: (4S*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 483/484[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.15-8.24 (m, 1H), 6.91-7.01 (m, 1H), 6.51-6.57 (m, 1H), 6.00-6.08 (m, 1H), 4.95-5.05 (m, 2H), 4.85-4.94 (m, 2 H), 4.64-4.71 (m, 1H), 4.48-4.55 (m, 1H), 3.35 (s, 3H), 2.99-3.08 (m, 1H), 2.85 (d, J=4.89 Hz, 3H), 2.68-2.76 (m, 1H), 1.19-1.25 (m, 3H).

* pure but unknown stereochemistry

Compound 111_D2: (4R*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 483/484[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.16-8.22 (m, 1H), 6.91-7.00 (m, 1H), 6.53-6.59 (m, 1H), 6.11-6.20 (m, 1H), 5.02-5.12 (m, 1H), 4.85-4.98 (m, 3H), 4.69-4.76 (m, 1H), 4.47 (s, 1H), 3.35 (s, 3H), 3.00-3.08 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.69-2.76 (m, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 112_D1: (4S*,9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 456[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.73-7.79 (m, 1H), 7.57-7.64 (m, 1H), 7.10-7.19 (m, 1H), 6.67 (s, 1H), 6.01-6.10 (m, 1H), 4.81-5.12 (m, 4H), 4.64-4.74 (m, 1H), 4.51 (d, J=15.77 Hz, 1H), 3.35 (s, 3H), 2.98-3.08 (m, 1H), 2.86 (d, J=4.89 Hz, 3H), 2.66-2.75 (m, 1H), 1.20 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 112_D2: (4R*,9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H) dicarboxamide

LCMS: 456[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.75-7.80 (m, 1H), 7.59-7.66 (m, 1H), 7.11-7.18 (m, 1H), 6.80 (s, 1H), 6.12-6.19 (m, 1H), 5.08-5.16 (m, 1H), 4.87-4.99 (m, 3H), 4.68-4.75 (m, 1H), 4.42 (d, J=15.69 Hz, 1H), 3.35 (s, 3H), 2.98-3.06 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.68-2.76 (m, 1H), 1.15-1.20 (m, 3H).

* pure but unknown stereochemistry

Compound 113: 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. Preparation of [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl methanesulfonate

A mixture of N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 031, 1.00 g, 2.36 mmol, 1.00 eq) and TEA (1.19 g, 11.80 mmol, 1.64 mL, 5.00 eq) in DCM (10.00 mL) was added MsCl (1.08 g, 9.44 mmol, 730.64 μL 4.00 eq) at 0° C. under N₂, and then the mixture was stirred at 30° C. for 2 hour under N₂ atmosphere. TLC showed the starting material was consumed completely and a new spot formed. The mixture was poured into ice-water (20 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (10 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (1.40 g, crude) as a yellow solid. LCMS: 502/504 [M+1].

Step 2, 4-(azidomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A solution of [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methylmethanesulfonate (1.18 g, 2.35 mmol, 1.00 eq) in DMF (15.00 mL) was added NaN₃ (458.51 mg, 7.05 mmol, 247.84 μL 3.00 eq) at 0° C. under N₂, and then the mixture was stirred at 50° C. for 16 hr under N₂ atmosphere. LCMS showed starting material/desired product=1/1. Then NaN₃ (458.32 mg, 7.05 mmol, 3.00 eq) was added to the mixture at 0° C. under N₂, and the mixture was stirred at 70° C. for another 16 hr. LCMS showed the starting material was consumed completely, desired product was major. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL,*3). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo to give the title compound (1.40 g, crude) as a yellow oil. LCMS: 449/451 [M+1]

Step 3, 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A solution of 4-(azidomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (1.06 g, 2.36 mmol, 1.00 eq) in THF (12.00 mL) and H₂O (2.00 mL) was added PPh₃ (1.24 g, 4.72 mmol, 2.00 eq), and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (30 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=100/1 to 20:1) to give the title compound (702.00 mg, 1.49 mmol, 63.31% yield, 90% purity) as a yellow solid, 75 mg of which was further purified by Prep-HPLC to give 25 mg pure desired product. LCMS: 423/425 [M+1]; ¹H NMR (400 MHz, METHANOL-d₄) δ 7.55-7.63 (m, 1H), 7.26-7.34 (m, 1H), 7.14 (s, 1H), 4.72 (br d, J=2.13 Hz, 4H), 4.38-4.47 (m, 1H), 3.73-3.92 (m, 2H), 3.33 (s, 3H), 2.96-3.18 (m, 2H), 2.80-2.87 (m, 2H).

Compound 114_E1: (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. 4-(azidomethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 28, 120.00 mg, 317.97 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 42.48 eq), and then the mixture was stirred at 25° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give the title compound (124.00 mg, 316.89 μmol, 99.66% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. Preparation of 4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of 4-(azidomethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (124.00 mg, 316.89 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (81.20 mg, 316.89 μmol, 1.00 eq), TEA (96.20 mg, 950.67 μmol, 131.78 μL 3.00 eq) in DCM (5.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 25° C. for 16 hour under N₂ atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1:2) to give the title compound (115.00 mg, 235.55 μmol, 74.33% yield, 90% purity) as a yellow solid. LCMS: 440[M+1].

Step 3, (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A solution of 4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (120.00 mg, 273.10 μmol, 1.00 eq) in THF (6.00 mL) and H₂O (1.00 mL) was added PPh₃ (143.26 mg, 546.20 μmol, 2.00 eq), and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely and the desired product was major. The mixture was poured into water (30 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=100/1 to 20:1), following by Prep-HPLC (HCl) to give the title compound (42.70 mg, 101.53 μmol, 37.18% yield, 98.3% purity) as a yellow solid.

LCMS: 414[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.76-7.83 (m, 1H), 7.66-7.72 (m, 1H), 7.27 (s, 1H), 4.67-4.82 (m, 4H), 4.38-4.47 (m, 1H), 3.75-3.93 (m, 2H), 3.40-3.67 (m, 1H), 3.33 (s, 3H), 3.05-3.19 (m, 1H), 2.79-2.89 (m, 2H)

Compound 115_D1: (4S*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. (9R)-4-(azidomethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 29, 120.00 mg, 306.57 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 44.06 eq), and then the mixture was stirred at 16° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give the title compound (124.00 mg, 305.92 μmol, 99.79% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2, (9R)-4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of (9R)-4-(azidomethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (124.00 mg, 305.92 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (78.39 mg, 305.92 μmol, 1.00 eq), TEA (92.87 mg, 917.77 μmol, 127.22 μL 3.00 eq) in DCM (5.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 25° C. for 16 hour under N₂ atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL). The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 1:2) to give the title compound (114.00 mg, 236.33 μmol, 77.25% yield, 94% purity) as a white solid. LCMS: 454[M+1]

Step 3, (4S*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A solution of (9R)-4-(azidomethyl)-N-(3-cyano-4-fluoro-phenyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (114.00 mg, 251.42 μmol, 1.00 eq) in THF (6.00 mL) and H₂O (1.00 mL) was added PPh₃ (131.89 mg, 502.83 μmol, 2.00 eq), and then the mixture was stirred at 15° C. for 16 hour under N₂ atmosphere. TLC showed the starting material was consumed completely, desired product was major. The mixture was poured into water (30 mL) and stirred at 5 min. The aqueous phase was extracted with ethyl acetate (15 mL*2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM/MeOH=100/1 to 20:1), following by Prep-HPLC (HCl) to give the title compound (13.00 mg, 27.52 μmol, 10.94% yield, 90.47% purity) as a yellow solid. LCMS: 428[M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.23 (br s, 2H), 7.91-7.98 (m, 1H), 7.75-7.84 (m, 1H), 7.42 (t, J=9.10 Hz, 1H), 4.98-5.11 (m, 1H), 4.72 (br s, 3H), 4.31-4.43 (m, 1H), 4.11-4.21 (m, 1H), 3.28 (s, 3H), 3.03-3.19 (m, 2H), 2.88-2.95 (m, 1H), 2.61 (br d, J=15.81 Hz, 1H), 1.10 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compound 115_D2: (4R*,9R)-4-(aminomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 115_D2 was prepared using the other enantiomer of Intermediate 29.

LCMS: 428[M+1]. ¹H NMR (400 MHz, DMSO-d6) δ 9.06 (br s, 1H), 8.23 (br s, 2H), 7.91-7.98 (m, 1H), 7.75-7.84 (m, 1H), 7.42 (t, J=9.10 Hz, 1H), 4.98-5.11 (m, 1H), 4.72 (br s, 3H), 4.31-4.43 (m, 1H), 4.11-4.21 (m, 1H), 3.28 (s, 3H), 3.03-3.19 (m, 2H), 2.88-2.95 (m, 1H), 2.61 (br d, J=15.81 Hz, 1H), 1.10 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compounds 116 and 117 were prepared in an analogous manner to Compound 115.

Compound 116_D1: (4S*,9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 471 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.77 (dd, J=2.45, 6.21 Hz, 1H), 7.54-7.67 (m, 1H), 7.54-7.69 (m, 1H), 7.24 (t, J=9.66 Hz, 1H), 5.03 (d, J=17.07 Hz, 1H), 4.93 (br d, J=5.77 Hz, 1H), 4.77-4.81 (m, 1H), 4.72 (br dd, J=6.09, 14.87 Hz, 1H), 4.31-4.50 (m, 2H), 3.32-3.37 (m, 4H), 2.97-3.16 (m, 2H), 2.69 (br d, J=15.69 Hz, 1H), 1.23 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 116_D2: (4R*,9R)-4-(aminomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 471[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.78 (dd, J=2.75, 6.17 Hz, 1H), 7.61-7.68 (m, 1H), 7.20-7.28 (m, 1H), 5.09 (s, 1H), 4.92-4.96 (m, 1H), 4.75-4.81 (m, 1H), 4.66-4.74 (m, 1H), 4.39-4.47 (m, 1H), 4.29-4.37 (m, 1H), 3.34 (s, 4H), 3.13-3.21 (m, 1H), 2.99-3.08 (m, 1H), 2.63-2.72 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

Compound 117_D1: (4S*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 481/483[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.72 (dd, J=2.64, 6.27 Hz, 1H), 7.33 (td, J=3.40, 8.88 Hz, 1H), 7.12 (t, J=8.72 Hz, 1H), 5.01 (brd, J=16.81 Hz, 1H), 4.90-4.92 (m, 1H), 4.63-4.77 (m, 1H), 4.29-4.50 (m, 2H), 3.32-3.39 (m, 1H), 3.32-3.38 (m, 3H), 2.95-3.13 (m, 2H), 2.68 (d, J=16.06 Hz, 1H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 117_D2: (4R*,9R)-4-(aminomethyl)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 481/483[M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.68-7.76 (m, 1H), 7.30-7.38 (m, 1H), 7.12 (t, J=8.68 Hz, 1H), 5.09 (d, J=16.87 Hz, 1H), 4.90-4.95 (m, 1H), 4.75-4.82 (m, 1H), 4.66-4.75 (m, 1H), 4.43 (dd, J=4.89, 14.79 Hz, 1H), 4.31 (d, J=16.87 Hz, 1H), 3.34 (s, 4H), 3.12-3.23 (m, 1H), 2.98-3.08 (m, 1H), 2.67 (br d, J=15.89 Hz, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 118: N10-(3-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. Preparation of tert-butyl 2-methyl-4-(methylcarbamoyl)-1-oxo-5,7,7a,8,9,11,11a,11b-octahydro-4H-pyrido[1,2]pyrazolo[3,5-c][1,2,5]oxadiazepine-10-carboxylate

A mixture of 10-(tert-butoxycarbonyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4-carboxylic acid (Intermediate 26, 500.00 mg, 1.35 mmol, 1.00 eq), T₃P (1.72 g, 2.70 mmol, 1.61 mL, 50% purity, 2.00 eq) and Et₃N (1.37 g, 13.50 mmol, 1.87 mL, 10.00 eq) in THF (8.00 mL) was added to methanamine; hydrochloride (455.72 mg, 6.75 mmol, 5.00 eq). The mixture was stirred at 70° C. for 16 h under N₂ in a sealed tube. The mixture was adjusted with HCl (1 M) to pH=6, then diluted with H₂O (20 mL) and extracted Ethyl acetate (20 mL*2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Petroleum ether:Ethyl acetate=1:3) to afford the title compound (235.00 mg, 612.87 μmol, 45.40% yield) as yellow solid. LCMS: 380 [M+1]

Step 2. Preparation of N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide

To a solution of tert-butyl 2-methyl-4-(methylcarbamoyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (259.00 mg, 682.64 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (4.43 g, 38.87 mmol, 2.88 mL, 56.94 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (268.00 mg, 681.38 μmol, 99.82% yield, TFA) as yellow oil, the crude product was used directly for the next step. LCMS: 280 [M+1].

Step 3, N10-(3-chloro-2,4-difluoro-phenyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a solution of N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (60.00 mg, 152.55 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added phenyl N-(3-chloro-2,4-difluoro-phenyl) carbamate (64.91 mg, 228.82 μmol, 1.50 eq) and Et₃N (77.18 mg, 762.74 μmol, 105.73 μL 5.00 eq). The mixture was stirred at 25° C. for 16 h. The mixture was adjusted to pH=6 with FA, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (FA), following by prep-TLC (DCM/MeOH=10/l) and prep-HPLC (FA) to afford (20.00 mg, 42.23 μmol, 27.68% yield, 99% purity) as white solid. LCMS [M+1]: 469/471. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (dt, J=5.52, 8.97 Hz, 1H), 6.96 (ddd, J=2.13, 8.41, 9.29 Hz, 1H), 6.57 (br d, J=2.76 Hz, 1H), 6.08 (br d, J=5.02 Hz, 1H), 4.86-5.00 (m, 2H), 4.61-4.82 (m, 3H), 3.93 (td, J=5.49, 13.74 Hz, 1H), 3.72-3.82 (m, 1H), 3.34 (s, 3H), 2.80-2.94 (m, 5H).

Compounds 195, 119, and 120 were prepared in an analogous manner to Compound 118.

Compound 119: N10-(5-chloro-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 469/471. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (t, J=8.03 Hz, 1H), 6.95 (dd, J=8.41, 10.54 Hz, 1H), 6.57 (br d, J=3.14 Hz, 1H), 6.07 (br d, J=4.39 Hz, 1H), 4.87-4.99 (m, 2H), 4.64-4.77 (m, 3H), 3.92 (td, J=5.52, 13.68 Hz, 1H), 3.70-3.81 (m, 1H), 3.34 (s, 3H), 2.81-2.93 (m, 5H).

Compound 120: N10-(3-cyano-4-fluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 442. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.75 (dd, J=2.76, 5.40 Hz, 1H), 7.61 (ddd, J=2.82, 4.58, 9.16 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.77 (s, 1H), 6.10 (br d, J=4.89 Hz, 1H), 4.85-5.00 (m, 2H), 4.62-4.76 (m, 3H), 3.77-3.93 (m, 2H), 3.34 (s, 3H), 2.81-2.93 (m, 5H).

Compound 121_D1: (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl (9R)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate

To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 700 mg, 1.91 mmol, 1.00 eq, single diastereomer separated by SFC) in DMF (5.00 mL) was added NaH (152.80 mg, 3.82 mmol, 60% purity, 2.00 eq) at −40° C. The mixture was stirred at −40° C. for 30 min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (1.23 g, 5.73 mmol, 3.00 eq) in was added dropwise at −40° C. The mixture was stirred at −20° C. for 0.5 hr. TLC (PE:ethyl acetate=1:1) showed the starting material consumed nearly and a new spot formed. The mixture was added into ice-water (50 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with H₂O (50 mL*3), dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified through column chromatography (PE:ethyl acetate: 30%˜50%) to get the title compound (580.00 mg, 1.35 mmol, 70.55% yield) as colorless oil.

Step 2. Preparation of (9R)-2-(2,2-difluoroethyl)-4-(hydroxymethyl)-9-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl (9R)-2-(2,2-difluoroethyl)-4-(hydroxymethyl)-9-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (440.00 mg, 1.06 mmol, 1.00 eq) in DCM (5.00 mL) was added TFA (8.06 g, 70.65 mmol, 5.23 mL, 66.86 eq). The mixture was stirred at 20° C. for 1 hr. TLC (PE:ethyl acetate=1:1) showed the starting material consumed. The mixture was concentrated in vacuum to get the title compound (460.00 mg, crude, TFA) as brown oil.

Step 3. (4S*,9R)—N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of (9R)-4-(2,2-difluoroethoxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (55.00 mg, 123.78 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (34.53 mg, 129.97 μmol, 1.05 eq) in DCM (3.00 mL) was added TEA (75.15 mg, 742.68 μmol, 102.95 μL 6.00 eq) at 20° C. The mixture was stirred at 20° C. for 16 h. LCMS indicated desired product was detected. The mixture was directly concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford the title compound (42.30 mg, 82.17 μmol, 66.39% yield, 97.5% purity) as white solid.

LCMS: 502 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.64, 6.53 Hz, 1H), 7.16-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.49 (s, 1H), 6.45-6.46 (m, 1H), 5.73-6.07 (m, 1H), 5.08-5.18 (m, 1H), 5.08-5.18 (m, 1H), 4.82-4.83 (m, 1H), 4.35-4.70 (m, 4H), 3.65-3.81 (m, 4H), 3.31 (s, 3H), 3.01-3.04 (m, 1H), 2.66-2.70 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compounds 108, 122, 123, 124, 125, 126, and 127 were prepared in an analogous method to Compound 121.

Compound 121_D2: (4R*,9R)—N-(3-chloro-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 502. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.60 (dd, J=2.70, 6.59 Hz, 1H), 7.20 (ddd, J=2.76, 4.05, 8.88 Hz, 1H), 7.03-7.09 (m, 1H), 6.47 (s, 1H), 5.75-6.06 (m, 1H), 5.10-5.19 (m, 1H), 4.84 (d, J=15.43 Hz, 1H), 4.54-4.66 (m, 2H), 4.37-4.50 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.96, 15.87 Hz, 1H), 2.69 (d, J=15.94 Hz, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 122_D1: (4S*,9R)—N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 546/548 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 8=7.72 (dd, J=2.57, 6.09 Hz, 1H), 7.24-7.29 (m, 2H), 7.04 (t, J=8.47 Hz, 1H), 6.51 (br s, 1H), 5.73-6.06 (m, 1H), 5.13 (m, 1H), 4.83 (m, 1H), 4.35-4.68 (m, 4H), 3.64-3.81 (m, 4H), 3.50 (s, 1H), 3.31 (s, 3H), 3.04 (m, 1H), 2.68 (m, 1H), 1.18 (d, J=6.90 Hz, 3H).

Compound 122_D2: (4R*,9R)—N-(3-bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 546/548. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.73 (dd, J=2.64, 6.02 Hz, 1H), 7.23-7.27 (m, 1H), 7.05 (t, J=8.47 Hz, 1H), 6.45 (s, 1H), 5.74-6.06 (m, 1H), 5.14 (br t, J=6.59 Hz, 1H), 4.84 (d, J=15.56 Hz, 1H), 4.54-4.65 (m, 2H), 4.37-4.50 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=6.09, 16.12 Hz, 1H), 2.69 (d, J=16.31 Hz, 1H), 1.18 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 123_D1: (4S*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-difluoroethoxy)methyl)-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 547/549 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.02-8.21 (m, 2H), 6.99 (br s, 1H), 5.73-6.07 (m, 1H), 4.85-5.10 (m, 2H), 4.39-4.66 (m, 4H), 3.64-3.81 (m, 4H), 3.31 (s, 3H), 3.00-3.13 (m, 1H), 2.72 (br d, J=15.94 Hz, 1H), 1.23 (d, J=6.78 Hz, 3H).

* pure but unknown stereochemistry

Compound 123_D2: (4R*,9R)—N-(2-bromo-3-fluoropyridin-4-yl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 547/549. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.14-8.18 (m, 1H), 8.07 (d, J=5.52 Hz, 1H), 6.95 (br d, J=3.89 Hz, 1H), 5.74-6.07 (m, 1H), 5.07 (m, 1H), 4.92 (m, 1H), 4.35-4.66 (m, 4H), 3.69-3.87 (m, 4H), 3.31 (s, 3H), 3.06 (m, 1H), 2.73 (d, J=15.94 Hz, 1H), 1.23 (d, J=6.90 Hz, 3H.

Compound 124_D1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 493 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.77 (dd, J=2.76, 5.52 Hz, 1H), 7.59 (ddd, J=2.82, 4.55, 9.07 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.71 (s, 1H), 5.71-6.08 (m, 1H), 5.06-5.19 (m, 1H), 4.85 (d, J=15.69 Hz, 1H), 4.36-4.69 (m, 4H), 3.62-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.77, 15.94 Hz, 1H), 2.69 (d, J=15.81 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 124_D2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 493. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.79 (dd, J=2.76, 5.40 Hz, 1H), 7.59 (m, 1H), 7.11-7.18 (m, 1H), 6.64 (s, 1H), 5.74-6.06 (m, 1H), 5.15 (brt, J=6.21 Hz, 1H), 4.86 (d, J=15.43 Hz, 1H), 4.37-4.66 (m, 4H), 3.70-3.86 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.83, 15.75 Hz, 1H), 2.70 (d, J=16.31 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 125_D1: (4S*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 482 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.25 (br d, J=2.51 Hz, 1H), 7.08-7.14 (m, 1H), 6.93 (t, J=8.97 Hz, 1H), 6.38 (s, 1H), 5.74-6.07 (m, 1H), 5.14 (quin, J=6.40 Hz, 1H), 4.83 (d, J=15.69 Hz, 1H), 4.38-4.68 (m, 4H), 3.63-3.84 (m, 4H), 3.50 (s, 1H), 3.31 (s, 3H), 3.04 (dd, J=5.83, 15.87 Hz, 1H), 2.67 (d, J=15.81 Hz, 1H), 2.26 (d, J=1.63 Hz, 3H), 1.18 (d, J=6.90 Hz, 3H).

Compound 125_D2: (4R*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 482. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.26 (d, J=2.89 Hz, 1H), 7.11 (td, J=3.87, 8.19 Hz, 1H), 6.89-6.96 (m, 1H), 6.37 (s, 1H), 5.74-6.06 (m, 1H), 5.15 (m, J=6.34 Hz, 1H), 4.85 (d, J=15.56 Hz, 1H), 4.54-4.66 (m, 2H), 4.36-4.50 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.84, 16.00 Hz, 1H), 2.68 (d, J=16.06 Hz, 1H), 2.26 (d, J=1.76 Hz, 3H), 1.17 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 126_D1: (4S*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)AO-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 536 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.68 (dd, J=2.70, 6.09 Hz, 1H), 7.56-7.62 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.61 (s, 1H), 5.72-6.11 (m, 1H), 5.15 (quin, J=6.43 Hz, 1H), 4.85 (d, J=15.56 Hz, 1H), 4.36-4.70 (m, 4H), 3.65-3.83 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.84, 15.87 Hz, 1H), 2.69 (d, J=15.81 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 126_D2: (4R*,9R)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 536. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=2.82, 6.21 Hz, 1H), 7.56-7.62 (m, 1H), 7.14 (t, J=9.29 Hz, 1H), 6.59 (s, 1H), 5.75-6.06 (m, 1H), 5.16 (m, J=6.78 Hz, 1H), 4.87 (d, J=15.56 Hz, 1H), 4.54-4.66 (m, 2H), 4.38-4.52 (m, 2H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.04 (dd, J=5.65, 15.81 Hz, 1H), 2.70 (d, J=16.19 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

Compound 127_D1: (4S*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LC-MS: 520 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) 8=8.19 (t, J=8.09 Hz, 1H), 6.95 (dd, J=8.47, 10.60 Hz, 1H), 6.55 (br d, J=2.76 Hz, 1H), 5.64-6.18 (m, 1H), 4.79-5.25 (m, 2H), 4.34-4.67 (m, 4H), 3.59-3.86 (m, 4H), 3.26-3.41 (m, 3H), 3.05 (dd, J=5.77, 15.81 Hz, 1H), 2.70 (d, J=15.81 Hz, 1H), 1.21 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 127_D2: (4R*,9R)—N-(5-chloro-2,4-difluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS (M+1): 520/522. ¹H NMR (400 MHz, CHLOROFORM-d) δ=8.20 (t, J=8.09 Hz, 1H), 6.95 (dd, J=8.41, 10.54 Hz, 1H), 6.53 (br d, J=2.76 Hz, 1H), 5.74-6.06 (m, 1H), 5.06-5.14 (m, 1H), 4.88 (d, J=15.69 Hz, 1H), 4.37-4.63 (m, 4H), 3.71-3.85 (m, 4H), 3.31 (s, 3H), 3.05 (dd, J=5.83, 16.12 Hz, 1H), 2.71 (d, J=15.94 Hz, 1H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 128: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((trifluoromethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1 tert-butyl 2-methyl-1-oxo-4-((trifluoromethoxy)methyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyraz-olo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a reaction bottle, AgOTf (192.50 mg, 749.19 μmol, 3.00 eq), Select Fluor® (301.60 mg, 851.36 μmol, 1.50 eq), KF (131.90 mg, 2.27 mmol, 53.19 μL 4.00 eq), tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 200.00 mg, 567.57 μmol, 1.00 eq) were added successively in a nitrogen-filled glovebox. Then EtOAc (6.00 mL), 2-fluoropyridine (165.32 mg, 1.70 mmol, 146.30 μL 3.00 eq) and TMSCF₃ (242.12 mg, 1.70 mmol, 3.00 eq) were added successively under N₂ atmosphere. The reaction mixture was stirred at 20° C. for 16 h. Several peaks showed on LCMS and 23% starting material remained and 13% desired product detected. The mixture was extracted with EtOAc (20 mL*2) and H₂O (20 mL). The combined organic layer was dried over Na₂SO₄, filtrated. The filtrate was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get the title compound (30.00 mg, 71.36 μmol, 12.57% yield) as white solid.

Step 2. N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-(trifluoromethoxymethyl)-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of tert-butyl 2-methyl-1-oxo-4-(trifluoromethoxymethyl)-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (45.00 mg, 107.05 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (5.00 mL). The mixture was stirred at 20° C. for 5 hr. TLC (PE:EtOAc=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to get 2-methyl-4-(trifluoromethoxymethyl)-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (48.00 mg, crude, TFA) as brown oil. To a solution of 2-methyl-4-(trifluoromethoxymethyl)-4,5,8,9,10,11-hexaHydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (48.00 mg, 110.53 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added TEA (55.92 mg, 552.63 μmol, 76.60 μL 5.00 eq) followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (35.24 mg, 132.64 μmol, 1.20 eq). The mixture was stirred at 20° C. for 16 hr. LCMS showed one main peak with desired MS detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA), repurified by prep-TLC (PE:EtOAc=1:1), further purification by prep-HPLC (base) to get the title compound (28.00 mg, 56.31 μmol, 50.94% yield, 98.9% purity) as white solid.

1H NMR (400 MHz, CHLOROFORM-d) δ=7.59 (dd, J=2.69, 6.48 Hz, 1H), 7.18-7.25 (m, 1H), 7.03-7.11 (m, 1H), 6.61 (s, 1H), 4.68-4.78 (m, 3H), 4.59-4.67 (m, 1H), 4.39 (dd, J=6.60, 14.43 Hz, 1H), 4.14-4.22 (m, 1H), 4.05-4.13 (m, 1H), 3.80-3.94 (m, 2H), 3.32 (s, 3H), 2.88 (t, J=5.75 Hz, 2H)

LCMS: 492 [M+1].

Compound 129: N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 129 was prepared in an analogous manner to Compound 208.

LCMS: 527 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ=8.90 (s, 1H), 7.72 (dd, J=2.57, 6.85 Hz, 1H), 7.48 (br s, 1H), 7.41 (ddd, J=2.69, 4.28, 9.05 Hz, 1H), 7.24-7.33 (m, 1H), 4.58-4.68 (m, 3H), 4.51 (quin, J=6.39 Hz, 1H), 4.29 (dd, J=7.40, 14.37 Hz, 1H), 3.66-3.82 (m, 2H), 3.24 (s, 5H), 2.72 (br t, J=5.38 Hz, 2H), 2.60-2.66 (m, 1H), 0.88-1.00 (m, 4H).

Compound 130: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2-trifluoroethyl)sulfonamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Compound 130 was prepared in an analogous manner to Compound 208.

LCMS: 569 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ=8.90 (s, 1H), 7.72 (dd, J=2.51, 6.78 Hz, 1H), 7.41 (td, J=4.36, 7.22 Hz, 1H), 7.25-7.31 (m, 1H), 4.58-4.65 (m, 3H), 4.44-4.57 (m, 3H), 4.29 (dd, J=6.96, 14.24 Hz, 1H), 3.70-3.79 (m, 2H), 3.28-3.30 (m, 2H), 3.24 (s, 3H), 2.72 (br t, J=5.58 Hz, 2H), 2.70-2.76 (m, 1H)

Compound 131: N-(3-chloro-4-fluorophenyl)-4-(3,3-difluoroazetidine-1-carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. methyl 2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-4-carboxylate

To a solution of 10-(tert-butyl) 4-methyl 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxylate (Intermediate 22, 1.00 g, 2.63 mmol, 1.00 eq) in DCM (40.00 mL) was added TFA (135.08 mmol, 10.00 mL, 51.36 eq). The mixture was stirred at 10° C. for 1 hr. TLC (PE:ethyl acetate=0:1) showed the starting material consumed. The mixture was concentrated in vacuum to get the title compound (1.10 g, crude, TFA) as brown oil.

Step 2. methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate

To a mixture of methyl 2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-4-carboxylate (1.10 g, 2.79 mmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (741.15 mg, 2.79 mmol, 1.00 eq) in DCM (20.00 mL) was added TEA (1.41 g, 13.95 mmol, 1.93 mL, 5.00 eq). The mixture was heated to 20° C. for 16 hr. LCMS showed one main peak with desired MS was detected and TLC (PE:ethyl acetate=0:1) showed two spots formed. The mixture was diluted with H₂O (30 mL). The organic phase was dried over Na₂SO₄, filtrated and concentrated in vacuum. The residue was purified by flash chromatography (PE:ethyl acetate: 50%˜80%) to get the title compound (1.00 g, 2.21 mmol, 79.33% yield) as white solid.

Step 3, 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a solution of methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate (900.00 mg, 1.99 mmol, 1.00 eq) in DCE (10.00 mL) was added hydroxy(trimethyl)stannane (1.44 g, 7.96 mmol, 4.00 eq). The mixture was stirred at 50° C. for 16 hr. TLC (PE:ethyl acetate=0:1) showed the starting material consumed. The mixture was diluted with DCM (100 mL) and quenched by a aqueous solution of KF (500 mg, 5 mL). The mixture was dried over Na₂SO₄ and filtrated. The filtrate was concentrated in vacuum to get the title compound (700.00 mg, 1.60 mmol, 80.35% yield) as white solid.

Step 4. N-(3-chloro-4-fluoro-phenyl)-4-(3,3-difluoroazetidine-1-carbonyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a solution of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (80.00 mg, 182.73 μmol, 1.00 eq) in DMF (3.00 mL) was added 3,3-difluoroazetidine hydrochloride (94.68 mg, 730.92 μmol, 4.00 eq), followed by DIEA (296.00 mg, 2.29 mmol, 400.00 μL 12.53 eq), PyBOP (142.64 mg, 274.09 μmol, 1.50 eq) and HOBt (24.69 mg, 182.73 μmol, 1.00 eq). The mixture was stirred at 20° C. for 16 h. The mixture was diluted with 0.5 M HCl (30 mL) and extracted with ethyl acetate (20 mL*2), then washed with NaHCO₃ (30 mL). The combined organic was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (DCM:MeOH=15:1), followed by prep-HPLC (FA) to get the title compound (15.50 mg, 30.04 μmol, 16.44% yield, 99.4% purity) as white solid. LCMS [M+1]: 513. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.59 (m, 1H), 7.17-7.23 (m, 1H), 7.06 (s, 1H), 6.50-6.54 (m, 1H), 4.86-5.02 (m, 2H), 4.62-4.77 (m, 3H), 4.33-4.61 (m, 4H), 3.85 (s, 2H), 3.31 (s, 3H), 2.88 (br s, 2H).

Compounds 132, 134, 135, and 136 were prepared in an analogous manner to Compound 131.

Compound 132: N-(3-chloro-4-fluorophenyl-4-(3,3-difluoropyrrolidine-1-carbonyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS [M+1]: 527. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.55-7.59 (m, 1H), 7.19 (br s, 1H), 7.03-7.09 (m, 1H), 6.55 (s, 1H), 4.96-5.06 (m, 1H), 4.88-4.95 (m, 1H), 4.72-4.84 (m, 2H), 4.60-4.69 (m, 2H), 3.97-4.17 (m, 1H), 3.74-3.96 (m, 5H), 3.24 (s, 3H), 2.87 (br d, J=5.6 Hz, 2H), 2.36-2.61 (m, 2H).

Compound 133: N10-(3-chloro-4-fluorophenyl)-N4,2-dimethyl-1-oxo-N4-(2,2,2-trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

To a mixture of 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (80.00 mg, 182.73 μmol, 1.00 eq), 2,2,2-trifluoro-N-methyl-ethanamine (27.33 mg, 182.73 μmol, 1.00 eq, HCl) and 3-picoline (51.05 mg, 548.18 μmol, 53.18 μL 3.00 eq) in MeCN (5.00 mL) was added MsCl (29.30 mg, 255.82 μmol, 19.80 μL 1.40 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 20° C. for 0.5 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely and major desired product formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL). The organic layer was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC to give the title compound (42.00 mg, 78.03 μmol, 42.70% yield, 99% purity) as a white solid. LCMS [M+1]: 533. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.55-7.60 (m, 1H), 7.16-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.51 (s, 1H), 4.94-5.10 (m, 2H), 4.75 (s, 1H), 4.49-4.70 (m, 3H), 3.86 (s, 3H), 3.16-3.37 (m, 6H), 2.88 (&, J=6.02 Hz, 2H).

Compound 134: N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 515. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.61 (m, 1H), 7.16-7.23 (m, 1H), 7.06 (s, 1H), 6.55 (s, 1H), 6.04 (s, 1H), 5.03 (s, 2H), 4.74 (s, 1H), 4.65 (s, 2H), 3.93-4.15 (m, 1H), 3.86 (brt, J=5.7 Hz, 2H), 3.51-3.71 (m, 1H), 3.15-3.34 (m, 6H), 2.88 (br d, J=5.7 Hz, 2H).

Compound 135: N10-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-N4-(2,2,2-trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 519. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.54-7.58 (m, 1H), 7.17-7.23 (m, 1H), 7.07 (s, 1H), 6.47-6.52 (m, 1H), 6.34-6.41 (m, 1H), 4.95 (s, 2H), 4.72 (d, J=2.3 Hz, 3H), 3.78-4.04 (m, 4H), 3.35 (s, 3H), 2.86 (t, J=5.7 Hz, 2H).

Compound 136: N10-(3-chloro-4-fluorophenyl)-N4-(2,2-difluoroethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 501. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.18-7.25 (m, 1H), 7.04-7.11 (m, 1H), 6.57 (s, 1H), 6.37 (brt, J=6.17 Hz, 1H), 5.68-6.02 (m, 1H), 4.88-4.98 (m, 2H), 4.67-4.77 (m, 3H), 3.85 (t, J=5.81 Hz, 2H), 3.58-3.78 (m, 2H), 3.36 (s, 3H), 2.87 (t, J=5.75 Hz, 2H), 2.19 (s, 1H).

Compound 138_E1: (S*)-N-(3-chloro-2,6-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 320.00 mg, 908.08 μmol, 1.00 eq, sing enantiomer separated by SFC) in DCM (10.00 mL) was added TFA (7.70 g, 67.53 mmol, 5.00 mL, 74.37 eq) dropwise at 0° C., and then the mixture was stirred at 30° C. for 1 hour. TLC and LCMS showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum to give the title compound (332.60 mg, 908.02 μmol, 99.99% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. N-(3-chloro-2,6-difluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of 4-(hydroxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (40.00 mg, 109.20 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-2,6-difluoro-phenyl)carbamate (34.07 mg, 120.12 μmol, 1.10 eq), TEA (22.10 mg, 218.40 μmol, 30.27 μL 2.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to afford the title compound (25.00 mg, 56.58 μmol, 51.82% yield, 100% purity) as a white solid.

Compounds 137, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, and 151 were prepared in an analogous method to Compound 138.

Compound 137_E1: (S*)-N-(3-chloro-2,4,5-trifluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 460/462 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.95-8.05 (m, 1H), 6.64-6.70 (m, 1H), 4.74 (d, J=3.01 Hz, 2H), 4.50-4.63 (m, 2H), 4.37-4.48 (m, 1H), 3.72-3.94 (m, 4H), 3.33 (s, 3H), 2.88 (s, 2H).

* pure but unknown stereochemistry

Compound 138_E1: (S*)-N-(3-chloro-2,6-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 442/444 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.17-7.25 (m, 1H), 6.91 (br d, J=1.83 Hz, 1H), 6.08-6.16 (m, 1H), 4.79 (s, 2H), 4.56 (br d, J=12.59 Hz, 2H), 4.43 (s, 1H), 3.73-3.97 (m, 4H), 3.32 (s, 3H), 2.88 (t, J=5.69 Hz, 1H), 2.84-2.92 (m, 1H).

* pure but unknown stereochemistry

Compound 139_E1: (S*)-N-(5-chloro-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 424/426 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.14-8.19 (m, 1H), 6.90-7.04 (m, 2H), 6.68-6.73 (m, 1H), 4.74 (s, 2H), 4.55 (br d, J=13.18 Hz, 2H), 4.37-4.47 (m, 1H), 3.71-3.95 (m, 4H), 3.33 (s, 3H), 2.88 (t, J=5.77 Hz, 2H).

* pure but unknown stereochemistry

Compound 140_E1: (S*)-N-(5-bromo-2,3-difluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 486/488 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.10 (br s, 1H), 6.97-7.05 (m, 1H), 6.69-6.76 (m, 1H), 4.75 (s, 2H), 4.55 (br d, J=13.45 Hz, 2H), 4.43 (s, 1H), 3.72-3.95 (m, 4H), 3.33 (s, 3H), 2.88 (t, J=5.75 Hz, 2H), 1.53-1.64 (m, 1H).

* pure but unknown stereochemistry

Compound 141_E1: (S*)-N-(5-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 468/470 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.29-8.34 (m, 1H), 7.06-7.13 (m, 1H), 6.91-6.98 (m, 1H), 6.66-6.72 (m, 1H), 4.74 (s, 2H), 4.51-4.62 (m, 2H), 4.37-4.46 (m, 1H), 3.72-3.96 (m, 4H), 3.33 (s, 3H), 2.88 (s, 2H).

* pure but unknown stereochemistry

Compound 142_E1: (S*)-N-(2,4-difluoro-3-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 422 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.69-7.79 (m, 1H), 6.77-6.86 (m, 1H), 6.48-6.55 (m, 1H), 4.74 (s, 2H), 4.51-4.61 (m, 2H), 4.36-4.46 (m, 1H), 3.73-3.93 (m, 4H), 3.33 (s, 3H), 2.83-2.90 (m, 2H), 2.21 (s, 3H).

* pure but unknown stereochemistry

Compound 143_E1: (S*)-N-(2,4-difluoro-5-methylphenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 422 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.75-7.81 (m, 1H), 6.76-6.84 (m, 1H), 6.49 (br d, J=2.51 Hz, 1H), 4.73 (s, 2H), 4.50-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.86 (br d, J=14.81 Hz, 4H), 3.32 (s, 3H), 2.87 (t, J=5.71 Hz, 2H), 2.22 (s, 3H), 2.00-2.15 (m, 1H).

* pure but unknown stereochemistry

Compound 144_E1: (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,45-trifluoro-3-methylphenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 440 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.78-7.89 (m, 1H), 6.57-6.63 (m, 1H), 4.73 (s, 2H), 4.51-4.62 (m, 2H), 4.37-4.47 (m, 1H), 3.71-3.94 (m, 4H), 3.33 (s, 3H), 2.87 (s, 2H), 2.24 (t, J=1.90 Hz, 2H), 2.20-2.28 (m, 1H).

* pure but unknown stereochemistry

Compound 145_E1: (S*)-N-(5-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 415 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.29-8.36 (m, 1H), 7.41-7.46 (m, 1H), 7.35-7.40 (m, 1H), 6.91-6.95 (m, 1H), 4.77 (s, 2H), 4.50-4.64 (m, 2H), 4.37-4.48 (m, 1H), 3.72-3.96 (m, 4H), 3.33 (s, 3H), 2.89 (t, J=5.75 Hz, 2H), 1.84-1.92 (m, 1H).

* pure but unknown stereochemistry

Compound 146_E1: (S*)-N-(3-cyano-2-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 415 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.32-8.38 (m, 1H), 7.24-7.27 (m, 1H), 7.18-7.24 (m, 1H), 6.70-6.83 (m, 1H), 4.77 (s, 2H), 4.50-4.63 (m, 2H), 4.37-4.47 (m, 1H), 3.73-3.97 (m, 4H), 3.33 (s, 3H), 2.89 (t, J=5.75 Hz, 2H).

* pure but unknown stereochemistry

Compound 147_E1: (S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 476 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.35-8.42 (m, 1H), 6.95-7.05 (m, 1H), 6.59-6.67 (m, 1H), 4.75 (s, 2H), 4.56 (br d, J=12.23 Hz, 2H), 4.36-4.47 (m, 1H), 3.72-3.97 (m, 4H), 3.33 (s, 3H), 2.88 (t, J=5.75 Hz, 2H).

* pure but unknown stereochemistry

Compound 148_E1: (S*)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 458 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.47 (dd, J=2.01, 7.28 Hz, 1H), 7.24-7.27 (m, 1H), 7.14-7.21 (m, 1H), 6.80 (br d, J=3.76 Hz, 1H), 4.76 (s, 2H), 4.51-4.62 (m, 2H), 4.38-4.47 (m, 1H), 3.72-3.97 (m, 4H), 3.33 (s, 3H), 2.85-2.93 (m, 2H).

* pure but unknown stereochemistry

Compound 149_E1: (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 476 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.17-8.26 (m, 1H), 6.95-7.03 (m, 1H), 6.62-6.68 (m, 1H), 4.75 (d, J=2.13 Hz, 2H), 4.56 (br d, J=12.93 Hz, 2H), 4.43 (s, 1H), 3.73-3.94 (m, 4H), 3.33 (s, 3H), 2.88 (s, 2H).

* pure but unknown stereochemistry

Compound 150_E1: (S*)-N-(2-bromo-5-fluoropyridin-4-yl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 469/471 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.38-8.43 (m, 1H), 8.14 (d, J=2.13 Hz, 1H), 6.94-7.00 (m, 1H), 4.75 (d, J=3.26 Hz, 2H), 4.51-4.63 (m, 2H), 4.43 (br d, J=9.16 Hz, 1H), 3.72-3.96 (m, 4H), 3.33 (s, 3H), 2.89 (t, J=5.83 Hz, 2H).

* pure but unknown stereochemistry

Compound 151_E1: (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N-(2,3,4,5-tetrafluorophenyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 444 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.80-7.90 (m, 1H), 6.65 (br s, 1H), 4.74 (d, J=3.14 Hz, 2H), 4.51-4.62 (m, 2H), 4.38-4.48 (m, 1H), 3.85 (br d, J=5.65 Hz, 4H), 3.33 (s, 3H), 2.88 (t, J=5.83 Hz, 2H).

* pure but unknown stereochemistry

Compound 152_D1: (4S*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. (9R)-10-tert-butoxycarbonyl-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid

To a solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 500.00 mg, 1.36 mmol, 1.00 eq, diastereomer separated by SFC) and NMO (1.19 g, 10.20 mmol, 1.08 mL, 7.50 eq) in MeCN (10.00 mL) was added TPAP (119.49 mg, 340.00 μmol, 0.25 eq). The mixture was stirred at 30° C. for 12 hr. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (20 mL) and washed with tert-butyl methyl ether (10 mL), the aqueous layer was acidified by 0.5 N HCl to pH 3, extracted with DCM (20 mL*2), the organic layer was washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to give the title compound (520.00 mg, crude) as a black brown solid. LCMS: 381[M+1].

Step 2, tert-butyl (9R)-4[2,2-di fluoroethyl(methyl)carbamoyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a mixture of (9R)-10-tert-butoxycarbonyl-2,9-dimethyl-1-oxo-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylic acid (250.00 mg, 657.22 μmol, 1.00 eq), 2,2-difluoro-N-methyl-ethanamine (172.91 mg, 1.31 mmol, 2.00 eq, HCl), 3-picoline (183.62 mg, 1.97 mmol, 191.27 μL 3.00 eq) in MeCN (5.00 mL) was added MsCl (112.93 mg, 985.83 μmol, 76.30 μL 1.50 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 2 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 1/2) to give the title compound (244.00 mg, 517.37 μmol, 78.72% yield, 97% purity) as a white solid. LCMS: 458[M+1].

Step 3, (9R)—N-(2,2-difluoroethyl)-N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide

A solution of tert-butyl (9R)-4-[2,2-difluoroethyl(methyl)carbamoyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (180.00 mg, 393.47 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.85 g, 16.21 mmol, 1.20 mL, 41.19 eq), and then the mixture was stirred at 30° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give the title compound (185.47 mg, 393.46 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

Step 4. (9R)-N10-(3-chloro-2,4-difluoro-phenyl)-N4-(2,2-difluoro ethyl)-N4,2,9-trimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a mixture of (9R)—N-(2,2-difluoroethyl)-N,2,9-trimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (60.00 mg, 127.29 μmol, 1.00 eq, TFA), phenyl N-(3-chloro-2,4-difluoro-phen yl)carbamate (43.33 mg, 152.75 pmol, 1.20 eq), TEA (25.76 mg, 254.58 μmol, 35.29 μL 2.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (51.00 mg, 86.73 μmol, 68.13% yield, 93% purity) as a white solid. LCMS: 547/548[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (br d, J=5.50 Hz, 1H), 6.92-7.00 (m, 1H), 6.56 (br s, 1H), 6.04 (s, 1H), 4.94-5.16 (m, 4H), 4.59-4.70 (m, 1H), 4.42 (d, J=15.53 Hz, 1H), 3.94-4.10 (m, 1H), 3.60 (br dd, J=4.34, 13.02 Hz, 1H), 3.15-3.35 (m, 6H), 3.05-3.13 (m, 1H), 2.62-2.74 (m, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 152_D2: (4R*,9R)-N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 152_D2 was prepared in an analogous manner to Compound 152_D1 using the opposite enantiomer of Intermediate 18.

LCMS: 547/548[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.83-7.93 (m, 1H), 6.91-7.02 (m, 1H), 6.46-6.55 (m, 1H), 5.86-6.21 (m, 1H), 5.03 (s, 3H), 4.78-4.87 (m, 1H), 4.51-4.71 (m, 2H), 3.95-4.11 (m, 1H), 3.52-3.67 (m, 1H), 3.16-3.33 (m, 6H), 3.00-3.09 (m, 1H), 2.70-2.78 (m, 1H), 1.21-1.27 (m, 3H).

* pure but unknown stereochemistry

Compounds 153, 154, and 155 were prepared in an analogous manner to Compound 152.

Compound 153_D1: (4S*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 538[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.22-8.32 (m, 1H), 6.99-7.06 (m, 1H), 6.61-6.68 (m, 1H), 6.04 (s, 1H), 4.94-5.16 (m, 4H), 4.59-4.70 (m, 1H), 4.39-4.47 (m, 1H), 3.93-4.08 (m, 1H), 3.52-3.70 (m, 1H), 3.15-3.34 (m, 6H), 3.04-3.13 (m, 1H), 2.66-2.74 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

Compound 153_D2: (4R*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 538[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.24-8.37 (m, 1H), 6.97-7.09 (m, 1H), 6.50-6.62 (m, 1H), 6.04 (s, 1H), 5.03 (s, 3H), 4.53-4.87 (m, 3H), 3.95-4.12 (m, 1H), 3.53-3.69 (m, 1H), 3.16-3.33 (m, 6H), 2.99-3.09 (m, 1H), 2.70-2.79 (m, 1H), 1.24 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 154_D1: (4S*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 547/548[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (s, 1H), 6.92-6.99 (m, 1H), 6.56-6.61 (m, 1H), 5.87-6.21 (m, 1H), 4.93-5.17 (m, 4H), 4.60-4.70 (m, 1H), 4.41 (d, J=15.65 Hz, 1H), 3.94-4.18 (m, 1H), 3.51-3.73 (m, 1H), 3.14-3.34 (m, 6H), 3.06 (br d, J=5.75 Hz, 1H), 2.72 (s, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 154_D2: (4R*,9R)-N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 547/548[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.16-8.23 (m, 1H), 6.91-6.99 (m, 1H), 6.48-6.55 (m, 1H), 5.87-6.22 (m, 1H), 5.03 (s, 3H), 4.76-4.84 (m, 1H), 4.51-4.72 (m, 2H), 3.95-4.11 (m, 1H), 3.51-3.68 (m, 1H), 3.15-3.34 (m, 6H), 2.98-3.09 (m, 1H), 2.70-2.78 (m, 1H), 1.23 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 155_D1: (4S*,9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 520[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.78-7.83 (m, 1H), 7.58-7.65 (m, 1H), 7.14 (s, 1H), 6.84 (s, 1H), 5.85-6.26 (m, 1H), 4.89-5.23 (m, 4H), 4.60-4.72 (m, 1H), 4.39 (d, J=15.65 Hz, 1H), 3.95-4.14 (m, 1H), 3.52-3.75 (m, 1H), 3.15-3.35 (m, 6H), 3.02-3.11 (m, 1H), 2.71 (s, 1H), 1.13-1.22 (m, 3H).

* pure but unknown stereochemistry

Compound 155_D2: (4R*,9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 520[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.76 (s, 1H), 7.54-7.61 (m, 1H), 7.11-7.19 (m, 1H), 6.56-6.62 (m, 1H), 5.88-6.21 (m, 1H), 5.04 (s, 3H), 4.74-4.82 (m, 1H), 4.51-4.70 (m, 2H), 3.93-4.15 (m, 1H), 3.52-3.72 (m, 1H), 3.15-3.35 (m, 6H), 2.97-3.09 (m, 1H), 2.76 (s, 1H), 1.22 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 156_D1: (4S*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 156 was prepared in an analogous manner to Compound 110.

LCMS: 474[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.25-8.36 (m, 1H), 6.98-7.08 (m, 1H), 6.57-6.64 (m, 1H), 6.00-6.11 (m, 1H), 4.95-5.07 (m, 2H), 4.91 (s, 2H), 4.65-4.72 (m, 1H), 4.51-4.57 (m, 1H), 3.35 (s, 3H), 2.99-3.08 (m, 1H), 2.85 (d, J=4.89 Hz, 3H), 2.68-2.77 (m, 1H), 1.23 (d, J=6.85 Hz, 2H), 1.19-1.26 (m, 1H).

* pure but unknown stereochemistry

Compound 156_D2: (4R*,9R)-N10-(3-cyano-2,4-difluorophenyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS: 474[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.24-8.34 (m, 1H), 6.99-7.06 (m, 1H), 6.62-6.68 (m, 1H), 6.09-6.20 (m, 1H), 5.02-5.11 (m, 1H), 4.86-4.99 (m, 3H), 4.68-4.77 (m, 1H), 4.46 (d, J=15.89 Hz, 1H), 3.35 (s, 3H), 2.99-3.09 (m, 1H), 2.89 (d, J=4.89 Hz, 3H), 2.69-2.78 (m, 1H), 1.20 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 157_D1: (4S*,9R)—N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

Step 1. (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A solution of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 40.00 mg, 109.17 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 123.72 eq), and then the mixture was stirred at 20° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to afford the title compound (41.52 mg, 109.17 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

Step 2. (4S*,9R)—N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of (9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (41.00 mg, 107.80 μmol, 1.00 eq, TFA), phenylN-[2-fluoro-5-(trifluoromethyl)phenyl]carbamate (35.48 mg, 118.58 μmol, 1.10 eq), TEA (21.82 mg, 215.61 μmol, 29.89 μL 2.00 eq) in DCM (5.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to afford the title compound (35.00 mg, 73.50 μmol, 68.19% yield, 99% purity) as a white solid. LCMS: 472 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.48 (dd, J=1.90, 7.27 Hz, 1H), 7.24-7.27 (m, 1H), 7.17 (s, 1H), 6.73-6.81 (m, 1H), 5.05-5.17 (m, 1H), 4.87 (s, 1H), 4.52-4.64 (m, 3 H), 4.46 (s, 1H), 3.81-3.88 (m, 1H), 3.71-3.80 (m, 1H), 3.34 (s, 3H), 3.01-3.11 (m, 1H), 2.71 (d, J=15.89 Hz, 1H), 1.22 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 157_D2: (4R*,9R)—N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

¹H NMR (400 MHz, CHLOROFORM-d) δ 8.46-8.52 (m, 1H), 8.46-8.52 (m, 1H), 7.24-7.27 (m, 1H), 7.14-7.22 (m, 1H), 6.75-6.82 (m, 1H), 5.06-5.19 (m, 1H), 4.92 (s, 1H), 4.48-4.62 (m, 3H), 4.35-4.44 (m, 1H), 3.86-3.94 (m, 1H), 3.75-3.82 (m, 1H), 3.34 (s, 3H), 3.02-3.11 (m, 1H), 3.02-3.11 (m, 1H), 2.65-2.78 (m, 1H), 1.21 (d, J=6.85 Hz, 2H), 1.19-1.24 (m, 1H).

* pure but unknown stereochemistry

Compound 158: N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Step 1. N-(2,2-difluoroethyl)-N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide

To a solution of tert-butyl 4-[2,2-difluoroethyl(methyl)carbamoyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (150.00 mg, 338.26 μmol, 1.00 eq) in DCM (4.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 79.86 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (154.70 mg, 338.25 μmol, 100.00% yield, TFA) as yellow oil, the crude product was used directly for the next step. LCMS: 344 [M+1]

Step 2, N10-(3-chloro-2,4-difluoro-phenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide

To a solution of N-(2,2-difluoroethyl)-N,2-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxamide (50.00 mg, 109.33 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added phenyl N-(3-chloro-2,4-difluoro-phenyl)carbamate (46.52 mg, 164.00 μmol, 1.50 eq) and Et3N (55.32 mg, 546.65 μmol, 75.78 μL 5.00 eq). The mixture was stirred at 25° C. for 16 h. The mixture was adjusted to neutral condition (pH6) with FA and concentrated in vacuo. The resulting residue was purified by prep-HPLC(FA) to afforded N10-(3-chloro-2,4-difluoro-phenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide (40.00 mg, 74.31 μmol, 67.97% yield, 99% purity) as white solid. LCMS [M+1]: 533/535. ¹H NMR (400 MHz, CHLOROFORM-d) δ7.86-7.88 (m, 1H), 6.90-7.03 (m, 1H), 6.57 (br s, 1H), 5.85-6.22 (m, 1H), 4.94-5.12 (m, 2H), 4.58-4.84 (m, 3H), 3.76-4.13 (m, 3H), 3.50-3.69 (m, 1H), 3.13-3.37 (m, 6H), 2.80-2.98 (m, 2H).

Compounds 159, 160, and 161 were prepared in an analogous manner to 158.

Compound 159: N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]:533/535. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.17 (t, J=8.07 Hz, 1H), 6.95 (dd, J=8.44, 10.64 Hz, 1H), 6.59 (br d, J=2.81 Hz, 1H), 5.85-6.20 (m, 1H), 4.93-5.09 (m, 2H), 4.58-4.83 (m, 3H), 3.80-4.12 (m, 3H), 3.59 (br dd, J=4.28, 13.08 Hz, 1H), 3.12-3.34 (m, 6H), 2.82-2.96 (m, 2H).

Compound 160: N10-(3-cyano-4-fluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 506. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.54-7.63 (m, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.71 (s, 1H), 5.86-6.22 (m, 1H), 4.95-5.10 (m, 2H), 4.73-4.84 (m, 1H), 4.57-4.69 (m, 2H), 3.78-4.09 (m, 3H), 3.47-3.68 (m, 1H), 3.14-3.36 (m, 6H), 2.81-2.95 (m, 2H).

Compound 161: N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2-difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

LCMS [M+1]: 524. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (dt, J=5.90, 9.10 Hz, 1H), 7.02 (ddd, J=1.69, 8.00, 9.51 Hz, 1H), 6.63 (d, J=2.51 Hz, 1H), 5.83-6.20 (m, 1H), 4.95-5.10 (m, 2H), 4.58-4.85 (m, 3H), 3.79-4.09 (m, 3H), 3.52-3.69 (m, 1H), 3.13-3.34 (m, 6H), 2.79-2.97 (m, 2H).

Compound 162:-(acetamidomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

A mixture of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 80.00 mg, 189.20 μmol, 1.00 eq), TEA (95.72 mg, 946.00 μmol, 131.12 μL 5.00 eq) in DCM (3.00 mL) was added acetyl acetate (77.26 mg, 756.80 μmol, 70.88 μL 4.00 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 2 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into ice-water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give 4 the title compound (48.00 mg, 102.22 μmol, 54.03% yield, 99% purity) as a white solid. LCMS: 465/467 [M+1]. ¹H NMR (400 MHz, Acetone) δ 8.33-8.39 (m, 1H), 7.82-7.88 (m, 1H), 7.43-7.49 (m, 1H), 7.32-7.41 (m, 1H), 7.16 (t, J=9.10 Hz, 1H), 4.55-4.69 (m, 4H), 4.36 (s, 1H), 3.83 (s, 2H), 3.52-3.62 (m, 1H), 3.35-3.44 (m, 1H), 3.24 (s, 3H), 2.74-2.78 (m, 2H), 1.90 (s, 3H).

Compounds 163, 164, 165, and 166 were prepared by an analogous method.

Compound 163: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2-trifluoroacetamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 519/520 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.55-7.60 (m, 1H), 7.17-7.23 (m, 1H), 7.07 (s, 1H), 6.60-6.69 (m, 1H), 6.47-6.51 (m, 1H), 4.64-4.79 (m, 3H), 4.56-4.63 (m, 1H), 4.44-4.51 (m, 1H), 3.76-3.94 (m, 2H), 3.66 (s, 2H), 3.31 (s, 3H), 2.81-2.91 (m, 2H).

Compound 164: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(((trifluoromethyl)sulfonamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 555/556 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.54-7.60 (m, 1H), 7.17-7.24 (m, 1H), 7.06 (s, 1H), 6.58 (s, 1H), 4.67 (s, 4H), 4.43-4.49 (m, 1H), 3.76-3.95 (m, 2H), 3.39-3.51 (m, 2H), 3.31 (s, 3H), 2.81-2.89 (m, 2H), 2.81-2.89 (m, 2H).

Compound 165: N-(3-chloro-4-fluorophenyl)-2-methyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 501/502 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.57-7.62 (m, 1H), 7.21-7.26 (m, 1H), 7.02-7.09 (m, 1H), 6.79-6.84 (m, 1H), 5.16-5.25 (m, 1H), 4.69 (s, 3H), 4.51-4.58 (m, 1H), 4.38-4.45 (m, 1H), 3.76-3.95 (m, 2H), 3.35-3.45 (m, 1H), 3.23-3.33 (m, 1H), 3.19 (s, 3H), 3.03 (s, 3H), 2.85 (br s, 2H).

Compound 166: methyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

LCMS: 481/482 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.55-7.61 (m, 1H), 7.17-7.23 (m, 1H), 7.03-7.09 (m, 1H), 6.53-6.59 (m, 1H), 4.95-5.06 (m, 1H), 4.50-4.76 (m, 4H), 4.38 (br dd, J=4.39, 14.05 Hz, 1H), 3.79-3.94 (m, 2H), 3.72 (s, 3H), 3.39-3.49 (m, 2H), 3.30 (s, 3H), 2.85 (s, 2H).

Compound 167_E1: (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl 4-(aminomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(azidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 28, 850.00 mg, 2.25 mmol, 1.00 eq) in THF (12.00 mL) and H₂O (2.00 mL) was added PPh3 (1.18 g, 4.50 mmol, 2.00 eq). The mixture was stirred at 25° C. for 16 hr. LCMS showed the reactant consumed completely. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL*3), the organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude was purified by column chromatography to afford the title compound (790.00 mg, 2.25 mmol, 99.92% yield) as white solid.

Step 2. tert-butyl 4-(acetamidomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(aminomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (720.00 mg, 2.05 mmol, 1.00 eq) in DCM (10.00 mL) was added TEA (622.00 mg, 6.15 mmol, 852.05 μL 3.00 eq) and Ac₂O (251.01 mg, 2.46 mmol, 230.29 μL 1.20 eq). The mixture was stirred at 25° C. for 2 hr. TLC showed the reaction completed. The mixture was poured into water (20 mL), extracted with DCM (20 mL*3), the organic layer was washed with HCl (20 mL, 1N), brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford the title compound (770.00 mg, 1.96 mmol, 95.66% yield) as white solid

Step 3. N-[(2-methyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl)methyl]acetamide

To a solution of tert-butyl 4-(acetamidomethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (450.00 mg, 1.14 mmol, 1.00 eq) in DCM (4.00 mL) was added TFA (3.08 g, 27.02 mmol, 2.00 mL, 23.70 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (464.00 mg, 1.14 mmol, 99.92% yield, TFA) as yellow oil, which was used directly for the next step.

Step 4. (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of (3R)-10-(2,2-difluoroethyl)-3-methyl-2,3,4,7,8,9-hexahydro-1H-pyrido[2,3]pyrazolo[2,4-b][1,4]diazepin-11-one (55.00 mg, 138.08 μmol, 1.00 eq, TFA) and Et₃N (69.86 mg, 690.40 μmol, 95.70 μL 5.00 eq) in DCM (2.00 mL) was added phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (36.68 mg, 138.08 μmol, 1.00 eq), the mixture was stirred at 25° C. for 16 h. The mixture was adjusted to neutral condition (pH6) with FA and directly evaporated to give the residue. The residue was purified by prep-HPLC (FA) to afford the title compound (31.70 mg, 69.33 μmol, 50.21% yield, 99.7% purity) as white solid. LCMS: 474 [M+1], LCMS: 474 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.28 (dt, J=5.77, 9.10 Hz, 1H), 6.96-7.07 (m, 1H), 6.62 (d, J=2.64 Hz, 1H), 5.74 (br s, 1H), 4.68-4.82 (m, 2H), 4.59-4.66 (m, 1H), 4.50-4.56 (m, 1H), 4.36-4.57 (m, 1H), 3.76-3.96 (m, 2H), 3.42-3.59 (m, 2H), 3.31 (s, 3H), 2.81-2.92 (m, 2H), 2.02 (s, 3H).

Compounds 168, 169, 170, 171, 172, 173, 174, and 175 were prepared by an analogous manner to Compound 167.

Compound 168_E1: (S*)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 456 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.59 (ddd, J=2.82, 4.49, 9.13 Hz, 1H), 7.10-7.19 (m, 1H), 6.69 (s, 1H), 5.75 (br s, 1H), 4.68-4.78 (m, 2H), 4.59-4.67 (m, 1H), 4.36-4.57 (m, 2H), 3.82-3.92 (m, 2H), 3.43-3.58 (m, 2H), 3.31 (s, 3H), 2.82-2.91 (m, 2H), 2.02 (s, 3H).

* pure but unknown stereochemistry

Compound 169_E1: (S*)-4-(acetamidomethyl)-N-(3-chloro-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 483/485 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.87 (dt, J=5.58, 8.94 Hz, 1H), 6.90-7.02 (m, 1H), 6.56 (d, J=2.76 Hz, 1H), 5.77 (br s, 1H), 4.68-4.81 (m, 2H), 4.62 (quin, J=5.46 Hz, 1H), 4.35-4.56 (m, 2H), 3.76-3.95 (m, 2H), 3.42-3.57 (m, 2H), 3.30 (s, 3H), 2.79-2.92 (m, 2H), 2.01 (s, 3H).

Compound 170_E1: (S*)-4-(acetamidomethyl)-N-(3-bromo-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 527/529[M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.94 (dt, J=5.65, 8.97 Hz, 1H), 6.94 (ddd, J=2.07, 7.72, 9.41 Hz, 1H), 6.56 (d, J=3.01 Hz, 1H), 5.73 (br s, 1H), 4.70-4.80 (m, 2H), 4.58-4.67 (m, 1H), 4.34-4.57 (m, 2H), 3.74-3.97 (m, 2H), 3.43-3.60 (m, 2H), 3.30 (s, 3H), 2.81-2.93 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 171_E1: (S*)-4-(acetamidomethyl)-N-(3-bromo-4-fluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 509/511 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (dd, J=2.64, 6.02 Hz, 1H), 7.24-7.27 (m, 1H), 7.00-7.10 (m, 1H), 6.52 (s, 1H), 5.75 (br s, 1H), 4.67-4.78 (m, 2H), 4.59-4.66 (m, 1H), 4.35-4.57 (m, 2H), 3.76-3.94 (m, 2H), 3.44-3.61 (m, 2H), 3.30 (s, 3H), 2.80-2.91 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 172_E1: (S*)-4-(acetamidomethyl)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 517 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (dt, J=5.40, 8.91 Hz, 1H), 6.94-7.05 (m, 1H), 6.64 (br d, J=3.64 Hz, 1H), 5.75 (br s, 1H), 4.75 (d, J=1.51 Hz, 2H), 4.58-4.67 (m, 1H), 4.35-4.57 (m, 2H), 3.76-3.96 (m, 2H), 3.42-3.60 (m, 2H), 3.30 (s, 3H), 2.81-2.95 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 173_E1: (S*)-4-(acetamidomethyl)-N-(5-chloro-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 483/485 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (t, J=8.03 Hz, 1H), 6.95 (dd, J=8.47, 10.60 Hz, 1H), 6.56 (d, J=3.14 Hz, 1H), 5.74 (br s, 1H), 4.69-4.77 (m, 2H), 4.59-4.66 (m, 1H), 4.35-4.56 (m, 2H), 3.74-3.96 (m, 2H), 3.43-3.58 (m, 2H), 3.30 (s, 3H), 2.82-2.92 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 174_E1: (S*)-4-(acetamidomethyl)-N-(5-bromo-2,4-difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 527/529 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.27-8.36 (m, 1H), 6.94 (dd, J=7.91, 10.79 Hz, 1H), 6.56 (br d, J=3.14 Hz, 1H), 5.76 (br s, 1H), 4.73 (s, 2H), 4.62 (quin, J=5.43 Hz, 1H), 4.35-4.56 (m, 2H), 3.74-3.97 (m, 2H), 3.42-3.57 (m, 2H), 3.30 (s, 3H), 2.80-2.93 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 175_E1: (S*)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 499 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.67 (dd, J=2.76, 6.02 Hz, 1H), 7.54-7.62 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.66 (s, 1H), 5.76 (br s, 1H), 4.70-4.78 (m, 2H), 4.58-4.68 (m, 1H), 4.36-4.57 (m, 2H), 3.79-3.94 (m, 2H), 3.45-3.57 (m, 2H), 3.30 (s, 3H), 2.80-2.92 (m, 2H), 2.01 (s, 3H).

* pure but unknown stereochemistry

Compound 176_D1: (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl(9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl (9R)-4-(azidomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 29, 1.06 g, 2.71 mmol, 1.00 eq), PPh₃ (1.42 g, 5.42 mmol, 2.00 eq) in THF (12.00 mL) and H₂O (2.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 0:1) to give the title compound (827.00 mg, 2.20 mmol, 81.00% yield, 97% purity) as a white solid. LCMS: 366 [M+1]

Step 2. Preparation of tert-butyl (9R)-4-(acetamidomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl(9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (250.00 mg, 684.13 μmol, 1.00 eq), TEA (346.13 mg, 3.42 mmol, 474.16 μL 5.00 eq) in DCM (5.00 mL) was added Ac₂O (279.37 mg, 2.74 mmol, 256.30 μL 4.00 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 2 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum to give the title compound (270.00 mg, crude) as a white solid. LCMS: 408 [M+1].

Step 3, (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A solution of tert-butyl(9R)-4-(acetamidomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetra hydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (140.00 mg, 343.59 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 39.31 eq), and then the mixture was stirred at 30° C. for 1 hour. TLC showed the starting material was consumed completely and a new spot formed. The mixture was concentrated in vacuum to give N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]acetamide (144.78 mg, 343.59 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

Step 4. (4S*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A mixture of N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyra zolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]acetamide (70.00 mg, 166.12 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (42.57 mg, 166.12 μmol, 1.00 eq), TEA (50.43 mg, 498.36 μmol, 69.08 μL 3.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (30.00 mg, 61.98 μmol, 37.31% yield, 97% purity) as a white solid. LCMS: 470 [M+1] ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.04 (s, 1H), 7.77 (dd, J=2.76, 5.40 Hz, 1H), 7.56-7.63 (m, 1H), 7.14 (s, 1H), 6.67 (s, 1H), 5.74-5.86 (m, 1H), 5.06-5.22 (m, 1H), 4.77-4.87 (m, 1H), 4.62-4.70 (m, 1H), 4.49-4.59 (m, 2H), 4.39-4.47 (m, 1H), 3.50 (s, 2H), 3.31 (s, 3H), 2.97-3.07 (m, 1H), 2.66-2.75 (m, 1H), 2.01 (s, 3H), 1.20 (d, J=7.03 Hz, 3H).

* pure but unknown stereochemistry

Compound 176_D2: (4R*,9R)-4-(acetamidomethyl)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 470 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.78 (dd, J=2.69, 5.26 Hz, 1H), 7.56-7.66 (m, 1H), 7.14 (t, J=8.74 Hz, 1H), 6.78 (br s, 1H), 5.80 (br s, 1H), 5.14 (m, J=6.48 Hz, 1H), 4.90 (d, J=15.65 Hz, 1H), 4.63 (q, J=5.47 Hz, 1H), 4.51-4.58 (m, 1H), 4.37-4.46 (m, 2H), 3.50-3.57 (m, 2H), 3.31 (s, 3H), 3.04 (dd, J=5.87, 15.77 Hz, 1H), 2.68 (d, J=15.65 Hz, 1H), 2.02 (s, 3H), 1.18 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 177 was prepared in an analogous manner to 176.

Compound 177_D1: (4S*,9R)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 513 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.64-7.73 (m, 1H), 7.56-7.62 (m, 1H), 7.10-7.17 (m, 1H), 6.55-6.65 (m, 1H), 5.69-5.83 (m, 1H), 5.05-5.22 (m, 1H), 4.78-4.88 (m, 1H), 4.62-4.69 (m, 1H), 4.55 (s, 2H), 4.39-4.46 (m, 1H), 3.51 (br d, J=4.77 Hz, 2H), 3.31 (s, 3H), 3.01 (s, 1H), 2.70 (d, J=15.69 Hz, 1H), 1.97-2.05 (m, 3H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 177_D2: (4R*,9R)-4-(acetamidomethyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 513 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.69 (dd, J=2.69, 6.11 Hz, 1H), 7.57-7.63 (m, 1H), 7.13 (t, J=9.35 Hz, 1H), 6.68 (br s, 1H), 5.79 (br s, 1H), 5.15 (m, J=6.42 Hz, 1H), 4.91 (d, J=15.53 Hz, 1H), 4.59-4.67 (m, 1H), 4.51-4.58 (m, 1H), 4.36-4.48 (m, 2H), 3.47-3.60 (m, 2H), 3.31 (s, 3H), 3.04 (dd, J=5.87, 16.02 Hz, 1H), 2.67 (d, J=16.02 Hz, 1H), 2.02 (s, 3H), 1.18 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 178_D1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. Preparation of tert-butyl(9R)-4-(methanesulfonamidomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl (9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 30, 250.00 mg, 684.13 μmol, 1.00 eq), TEA (138.45 mg, 1.37 mmol, 189.66 μL 2.00 eq) in DCM (5.00 mL) was added MsCl (117.55 mg, 1.03 mmol, 79.43 μL 1.50 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 2 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into ice-water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-TLC (PE/EA=0/1) to give the title compound (218.00 mg, 471.86 μmol, 68.97% yield, 96% purity) as a white solid. LCMS: 444 [M+1]

Step 2. (4S*,9R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A mixture of tert-butyl(9R)-4-(methanesulfonamidomethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (109.00 mg, 245.76 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (2.31 g, 20.26 mmol, 1.50 mL, 82.44 eq), and then the mixture was stirred at 30° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give N-[[(9R)-2,9-dimethyl-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]methanesulfonamide (112.40 mg, 245.73 μmol, 99.99% yield, TFA) as a yellow oil, which was used directly for next step.

Step 3, 4S*,9R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

A mixture of N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyra zolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]methanesulfonamide (56.00 mg, 122.43 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (31.37 mg, 122.43 μmol, 1.00 eq), TEA (24.78 mg, 244.86 μmol, 33.95 μL 2.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (33.30 mg, 65.87 μmol, 53.80% yield, 100% purity) as a white solid. LCMS: 506 [M+1] ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.75-7.81 (m, 1H), 7.56-7.65 (m, 1H), 7.11-7.19 (m, 1H), 6.68-6.77 (m, 1H), 5.05-5.15 (m, 1H), 4.84-4.97 (m, 1H), 4.67-4.82 (m, 2H), 4.55 (br d, J=17.85 Hz, 3H), 3.31 (s, 5H), 3.01 (s, 4H), 2.64-2.73 (m, 1H), 1.19 (d, J=6.85 Hz, 3H).

* pure but unknown stereochemistry

Compound 178_D2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 506 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.80 (dd, J=2.76, 5.52 Hz, 1H), 7.58-7.67 (m, 1H), 7.15 (t, J=8.72 Hz, 1H), 6.78 (s, 1H), 5.16 (br t, J=6.40 Hz, 1H), 4.91 (s, 2H), 4.55-4.74 (m, 2H), 4.36-4.50 (m, 2H), 3.36-3.43 (m, 2H), 3.33 (s, 3H), 2.97-3.11 (m, 4H), 2.69 (d, J=15.94 Hz, 1H), 1.20 (d, J=7.03 Hz, 3H).

* pure but unknown stereochemistry

Compound 179 was prepared in an analogous manner to Compound 178.

Compound 179_D1: (4S*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 549 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.65-7.71 (m, 1H), 7.56-7.62 (m, 1H), 7.14 (s, 1H), 6.60 (s, 1H), 5.06-5.18 (m, 1H), 4.76-4.87 (m, 2H), 4.66-4.75 (m, 1H), 4.49-4.63 (m, 2H), 4.44 (d, J=3.42 Hz, 1H), 3.28-3.42 (m, 5H), 3.00 (s, 4H), 2.65-2.74 (m, 1H), 1.20 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 179_D2: (4R*,9R)—N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 549 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (dd, J=2.70, 6.21 Hz, 1H), 7.60 (brs, 1H), 7.15 (s, 1H), 6.69 (s, 1H), 5.17 (s, 1H), 4.93 (d, J=15.69 Hz, 1H), 4.86 (s, 1H), 4.56-4.74 (m, 2H), 4.34-4.50 (m, 2H), 3.36-3.44 (m, 2H), 3.33 (s, 3H), 3.01-3.10 (m, 4H), 2.69 (d, J=15.81 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 180_D1: methyl (((4S*,9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

Step 1. tert-butyl (9R)-4[(methoxycarbonylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl (9R)-4-(aminomethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 30, 250.00 mg, 684.13 μmol, 1.00 eq), TEA (346.14 mg, 3.42 mmol, 474.16 μL 5.00 eq) in DCM (5.00 mL) was added methyl carbonochloridate (258.60 mg, 2.74 mmol, 211.97 μL 4.00 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 2 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into ice-water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-TLC to give the title compound (180.00 mg, 412.32 μmol, 60.27% yield, 97% purity) as a white solid. LCMS: 424 [M+1].

Step 2, methyl N-[[(9R)-10-[(3-cyano-4-fluoro-phenyl)carbamoyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]carbamate

A mixture of tert-butyl(9R)-4-[(methoxycarbonylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (90.00 mg, 212.53 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 63.55 eq), and then the mixture was stirred at 30° C. for 1 hour. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was concentrated in vacuum to give methyl N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]carbamate (92.95 mg, 212.52 μmol, 100.00% yield, TFA) as a yellow oil, which was used directly for next step.

Step 3. methyl (((4S*,9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

A mixture of methyl N-[[(9R)-2,9-dimethyl-1-oxo-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-4-yl]methyl]carbamate (46.00 mg, 105.17 μmol, 1.00 eq, TFA), phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (26.95 mg, 105.17 μmol, 1.00 eq), TEA (21.28 mg, 210.34 μmol, 29.15 μL 2.00 eq) in DCM (3.00 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 30° C. for 16 hour under N₂ atmosphere. LCMS showed the starting material was consumed completely, desired product was major. The mixture was poured into water (10 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (5 mL*3). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by Prep-HPLC (FA) to give the title compound (36.40 mg, 74.23 μmol, 70.58% yield, 99% purity) as a white solid. LCMS: 486 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.78 (dd, J=2.81, 5.38 Hz, 1H), 7.55-7.62 (m, 1H), 7.14 (s, 1H), 6.62 (s, 1H), 5.08-5.20 (m, 1H), 4.92-5.02 (m, 1H), 4.79 (s, 1H), 4.37-4.66 (m, 4H), 3.72 (s, 3H), 3.44 (br d, J=5.38 Hz, 2H), 3.31 (s, 3H), 2.98-3.07 (m, 1H), 2.66-2.74 (m, 1H), 1.19 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 180_D2: methyl (((4R*,9R)-10-((3-cyano-4-fluorophenyl)carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

LCMS: 486 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.80 (dd, J=2.82, 5.46 Hz, 1H), 7.58-7.67 (m, 1H), 7.16 (t, J=8.66 Hz, 1H), 6.70 (s, 1H), 5.16 (br t, J=6.40 Hz, 1H), 5.00 (br s, 1H), 4.90 (d, J=15.56 Hz, 1H), 4.52-4.68 (m, 2H), 4.46 (br d, J=15.69 Hz, 2H), 3.73 (s, 3H), 3.42-3.57 (m, 2H), 3.33 (s, 3H), 3.00-3.10 (m, 1H), 2.70 (d, J=15.94 Hz, 1H), 1.20 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 181 was prepared in an analogous manner to Compound 180.

Compound 181_D1: methyl (((4S*,9R)-10-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

LCMS: 529 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.68 (br s, 1H), 7.56-7.62 (m, 1H), 7.14 (s, 1H), 6.56 (s, 1H), 5.08-5.22 (m, 1H), 4.92-5.02 (m, 1H), 4.82 (d, J=15.65 Hz, 1H), 4.55 (s, 4H), 3.72 (s, 3H), 3.36-3.52 (m, 2H), 3.31 (s, 3H), 2.98-3.08 (m, 1H), 2.69 (d, J=15.89 Hz, 1H), 1.19 (d, J=6.97 Hz, 3H).

* pure but unknown stereochemistry

Compound 181_D2: methyl (((4R*,9R)-10-((4-fluoro-3-(trifluoromethyl)phenyl)carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

LCMS: 529 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.70 (dd, J=2.70, 6.21 Hz, 1H), 7.58-7.65 (m, 1H), 7.15 (s, 1H), 6.63 (s, 1H), 5.11-5.23 (m, 1H), 4.95-5.04 (m, 1H), 4.91 (d, J=15.56 Hz, 1H), 4.58 (br d, J=13.68 Hz, 2H), 4.47 (br d, J=15.56 Hz, 2H), 3.73 (s, 3H), 3.48 (br d, J=5.27 Hz, 2H), 3.33 (s, 3H), 3.01-3.11 (m, 1H), 2.70 (d, J=15.69 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 182_D1: (4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

A mixture of tert-butyl (9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 18, 3.00 g, 8.19 mmol, 1.00 eq), TEA (4.14 g, 40.95 mmol, 5.67 mL, 5.00 eq) in DCM (40.00 mL) was added MsCl (3.75 g, 32.76 mmol, 2.53 mL, 4.00 eq) dropwise at 0° C. under N₂, and then the mixture was stirred at 30° C. for 3 hour under N₂ atmosphere. TLC showed the starting material was consumed completely, a new spot appeared. The mixture was poured into ice-water (50 mL) and stirred at 5 min. The aqueous phase was extracted with DCM (40 mL*2). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 1:2) to give the title compound (3.40 g, 7.34 mmol, 89.66% yield, 96% purity) as a white solid.

LCMS: 445 [M+1].

Step 2, tert-butyl (9R)-4-[(2,2-difluoroethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl (9R)-2,9-dimethyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (1.10 g, 2.47 mmol, 1.00 eq) in DMSO (12.00 mL) was added 2,2-difluoroethanamine (12.01 g, 148.20 mmol, 60.00 eq), the mixture was stirred at 90° C. for 72 h. LCMS showed that the reactant was remained, the mixture was stirred at 90° C. for 24 h. The mixture was diluted with H₂O 30 mL and extracted with EtOAc (30 mL*2). The combined organic layers were washed with brine (30 mL*3), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purification by column chromatography (PE:EtOAc=1:2) to afford the title compound (510.00 mg, 1.01 mmol, 40.87% yield, 85% purity) as yellow oil.

Step 3. (9R)-4-[(2,2-difluoroethylamino)methyl]-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl (9R)-4-[(2,2-difluoroethylamino)methyl]-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4Hpyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (220.00 mg, 512.27 μmol, 1.00 eq) in DCM (8.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 52.73 eq), the reaction mixture was stirred at 25° C. for one hour. TLC indicated starting material was consumed completely. Removed the solvent on a rotary evaporator to give the title compound (220.00 mg, crude, TFA) as yellow oil, used in the next step directly without purification.

Step 3. (4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a mixture of (9R)-4-[(2,2-difluoroethylamino)methyl]-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (55.00 mg, 124.05 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (50.21 mg, 496.20 μmol, 68.78 μL 4.00 eq), followed by phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl] carbamate (37.12 mg, 124.05 μmol, 1.00 eq), the reaction mixture was stirred at 25° C. for 4 hours. Several new peaks were shown on LCMS and 40% of desired compound was detected. Removed the solvent on a rotary evaporator. The residue was purified by prep-HPLC(HCl) to give the title compound (15.00 mg, 27.22 μmol, 21.95% yield, 97% purity) as white solid. LCMS: 571 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 9.03-9.10 (m, 1H), 9.06 (s, 1H), 7.88-7.96 (m, 1H), 7.75-7.84 (m, 1H), 7.41 (d, J=9.91 Hz, 1H), 6.23-6.62 (m, 1H), 4.94-5.10 (m, 2H), 4.82-4.93 (m, 1H), 4.70 (dd, J=6.09, 14.87 Hz, 1H), 4.44 (dd, J=4.45, 14.87 Hz, 1H), 4.18 (d, J=17.19 Hz, 1H), 3.47-3.62 (m, 2H), 3.29 (s, 3H), 3.14-3.24 (m, 2H), 2.86-2.96 (m, 1H), 2.57-2.69 (m, 2H), 2.30-2.36 (m, 1H), 1.11 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compound 182_D2: (4R*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 535 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.78 (dd, J=2.57, 6.34 Hz, 1H), 7.62-7.68 (m, 1H), 7.24 (t, J=9.66 Hz, 1H), 6.19-6.50 (m, 1H), 5.13 (d, J=16.81 Hz, 1H), 4.95 (br d, J=6.78 Hz, 2H), 4.74 (dd, J=6.02, 14.93 Hz, 1H), 4.46 (dd, J=3.83, 15.00 Hz, 1H), 4.31 (d, J=16.81 Hz, 1H), 3.67 (dt, J=2.89, 15.50 Hz, 2H), 3.55 (dd, J=2.64, 13.68 Hz, 1H), 3.38-3.44 (m, 1H), 3.36 (s, 3H), 3.05 (dd, J=5.90, 16.06 Hz, 1H), 2.68 (d, J=15.94 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H).

* pure but unknown stereochemistry

Compounds 183, 184, and 185 were prepared in an analogous manner to Compound 182.

Compound 183_D1: (4S*,9R)—N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 528 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 7.91-7.98 (m, 1H), 7.76-7.84 (m, 1H), 7.43 (t, J=9.10 Hz, 1H), 6.24-6.62 (m, 1H), 5.02 (br d, J=17.19 Hz, 2H), 4.82-4.92 (m, 1H), 4.68 (br d, J=5.90 Hz, 1H), 4.40-4.49 (m, 1H), 4.18 (br d, J=17.32 Hz, 1H), 3.50-3.64 (m, 1H), 3.29 (s, 3H), 3.13-3.24 (m, 2H), 2.85-2.95 (m, 1H), 2.58-2.69 (m, 2H), 2.31-2.34 (m, 1H), 1.07-1.15 (m, 3H).

* pure but unknown stereochemistry

Compound 183_D2: (4R*,9R)—N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 492 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.79 (dd, J=2.76, 5.40 Hz, 1H), 7.60 (ddd, J=2.82, 4.52, 9.10 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.74 (s, 1H), 5.69-6.02 (m, 1H), 5.10-5.20 (m, 1H), 4.89 (d, J=15.56 Hz, 1H), 4.51-4.60 (m, 2H), 4.35-4.48 (m, 2H), 3.32 (s, 3H), 2.98-3.11 (m, 4H), 2.87 (dd, J=4.45, 12.99 Hz, 1H), 2.69 (d, J=16.19 Hz, 1H), 1.19 (d, J=6.90 Hz, 3H)

* pure but unknown stereochemistry

Compound 184_D1: (4S*,9R)—N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino) methyl-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 581 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 7.85 (dd, J=2.64, 6.40 Hz, 1H), 7.42-7.50 (m, 1H), 7.26 (t, J=8.85 Hz, 1H), 6.23-6.61 (m, 1H), 5.01 (br d, J=17.07 Hz, 2H), 4.81-4.90 (m, 1H), 4.68 (br d, J=6.15 Hz, 1H), 4.46 (br d, J=4.27 Hz, 1H), 4.16 (d, J=17.19 Hz, 1H), 3.56 (br s, 2H), 3.29 (s, 3H), 3.17-3.23 (m, 2H), 2.85-2.95 (m, 1H), 2.65-2.70 (m, 1H), 2.56-2.63 (m, 1H), 2.28-2.36 (m, 1H), 1.10 (d, J=6.78 Hz, 3H)

* pure but unknown stereochemistry

Compound 184_D2: (4R*,9R)—N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino) methyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 545/547 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.73 (dd, J=2.57, 6.09 Hz, 1H), 7.29 (br d, J=3.01 Hz, 1H), 7.05 (t, J=8.53 Hz, 1H), 6.57 (br s, 1H), 5.69-6.02 (m, 1H), 5.09-5.20 (m, 1H), 4.87 (d, J=15.56 Hz, 1H), 4.31-4.62 (m, 4H), 3.32 (s, 3H), 2.96-3.13 (m, 4H), 2.86 (dd, J=4.33, 12.99 Hz, 1H), 2.68 (d, J=15.81 Hz, 1H), 1.18 (d, J=6.90 Hz, 3H)

* pure but unknown stereochemistry

Compound 185_D1: (4S*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 517 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ 7.18-7.24 (m, 1H), 7.13 (br d, J=4.40 Hz, 1H), 6.93 (t, J=9.11 Hz, 1H), 6.32 (s, 1H), 4.95-5.05 (m, 2H), 4.90-4.93 (m, 2H), 4.70-4.80 (m, 1H), 4.31-4.52 (m, 2H), 3.50-3.70 (m, 3H), 3.35 (s, 3H), 2.94-3.06 (m, 1H), 2.59-2.76 (m, 1H), 2.23 (d, J=1.83 Hz, 3H), 1.22 (d, J=6.85 Hz, 3H)

Compound 185_D2: (4R*,9R)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 481 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.26 (br s, 1H), 7.09-7.15 (m, 1H), 6.93 (t, J=9.03 Hz, 1H), 6.41 (s, 1H), 5.68-6.02 (m, 1H), 5.15 (quin, J=6.37 Hz, 1H), 4.87 (d, J=15.69 Hz, 1H), 4.50-4.61 (m, 2H), 4.31-4.48 (m, 2H), 3.31 (s, 3H), 2.96-3.12 (m, 4H), 2.86 (dd, J=4.33, 12.99 Hz, 1H), 2.67 (d, J=15.94 Hz, 1H), 2.26 (d, J=1.51 Hz, 3H), 1.17 (d, J=6.90 Hz, 3H)

* pure but unknown stereochemistry

Compound 186_E1: (S*)-N-(3-cyano-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxylate (Intermediate 1, 500.00 mg, 1.42 mmol, 1.00 eq) in DCM (2.00 mL) was added TEA (358.95 mg, 3.55 mmol, 491.72 μL 2.50 eq) and MsCl (211.30 mg, 1.84 mmol, 142.77 μL 1.30 eq). Then the mixture was stirred 20° C. for 2 hr. TLC (Ethyl acetate) showed the reaction was complete. The reaction mixture was diluted with DCM (20 mL) and washed with brine (10 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to give tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (600.00 mg, 1.39 mmol, 98.16% yield) was obtained as yellow solid, which was used in the next step without further purification.

Step 2. tert-butyl4-[(2,2-difluoroethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a solution of tert-butyl 2-methyl-4-(methylsulfonyloxymethyl)-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (640.00 mg, 1.49 mmol, 1.00 eq) in DMSO (15.00 mL) was added 2,2-difluoroethanamine (7.25 g, 89.40 mmol, 60.00 eq). The mixture was stirred in a sealed tube at 90° C. for 72 hr. LCMS showed 82% desired product, 2% reactant and 4% by-product detected. The mixture was poured into water (50 mL), extracted with ethyl acetate (20 mL*3), the organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The crude was purified by column chromatography to afford the title compound (540.00 mg, 1.30 mmol, 87.24% yield) as yellow solid. LCMS: 416 [M+1].

Step 3, 4-[(2,2-difluoroethylamino)methyl]-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-[(2,2-difluoroethylamino)methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (70.00 mg, 168.50 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 80.16 eq) at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture was concentrated under reduced pressure to afford the title compound (80.00 mg, 147.23 μmol, 87.38% yield, 2TFA) as yellow oil, the crude product was used directly for the next step.

Step 4. (S*)-N-(3-cyano-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 4-[(2,2-difluoroethylamino)methyl]-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (80.00 mg, 147.23 μmol, 1.00 eq, 2TFA) in DCM (3.00 mL) was added phenyl N-[2,4-difluoro-3-(trifluoromethyl)phenyl]carbamate (56.04 mg, 176.68 μmol, 1.20 eq) and Et3N (74.49 mg, 736.16 μmol, 102.04 μL 5.00 eq). The mixture was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC(FA) to afford the title compound (29.00 mg, 50.63 μmol, 34.39% yield, 94% purity) as white solid. LCMS: 496 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (dt, J=5.90, 8.97 Hz, 1H), 7.02 (t, J=8.72 Hz, 1H), 6.60 (br s, 1H), 5.67-6.02 (m, 1H), 4.68-4.81 (m, 2H), 4.48-4.59 (m, 2H), 4.32-4.43 (m, 1H), 3.76-3.95 (m, 2H), 3.31 (s, 3H), 2.95-3.09 (m, 3H), 2.78-2.93 (m, 3H).

* pure but unknown stereochemistry

Compounds 187, 188, 189, 190, 191, 192, 193, and 194 were prepared in an analogous manner to Compound 186.

Compound 187_E1: (S*)-N-(3-cyano-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 478 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.77 (dd, J=2.76, 5.27 Hz, 1H), 7.53-7.62 (m, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.64 (s, 1H), 5.67-6.03 (m, 1H), 4.63-4.79 (m, 2H), 4.48-4.59 (m, 2H), 4.31-4.42 (m, 1H), 3.80-3.93 (m, 2H), 3.31 (s, 3H), 2.96-3.11 (m, 3H), 2.77-2.92 (m, 3H).

* pure but unknown stereochemistry

Compound 188_E1: (S*)-N-(3-chloro-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 505/507 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.88 (dt, J=5.52, 8.85 Hz, 1H), 6.89-7.01 (m, 1H), 6.54 (br s, 1H), 5.67-6.04 (m, 1H), 4.68-4.80 (m, 2H), 4.48-4.60 (m, 2H), 4.29-4.40 (m, 1H), 3.76-3.98 (m, 2H), 3.31 (s, 3H), 2.95-3.10 (m, 3H), 2.77-2.93 (m, 3H).

Compound 189_E1: (S*)-N-(3-bromo-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 549/551 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.95 (dt, J=5.83, 8.88 Hz, 1H), 6.94 (br t, J=8.47 Hz, 1H), 6.54 (br s, 1H), 5.68-6.02 (m, 1H), 4.67-4.81 (m, 2H), 4.47-4.61 (m, 2H), 4.30-4.42 (m, 1H), 3.75-3.95 (m, 2H), 3.31 (s, 3H), 2.94-3.09 (m, 3H), 2.77-2.92 (m, 3H).

* pure but unknown stereochemistry

Compound 190_E1: (S*)-N-(3-bromo-4-fluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 531/533 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.71 (dd, J=2.57, 5.96 Hz, 1H), 7.24 (br d, J=2.89 Hz, 1H), 7.05 (t, J=8.53 Hz, 1H), 6.48 (s, 1H), 5.68-6.03 (m, 1H), 4.63-4.76 (m, 2H), 4.49-4.59 (m, 2H), 4.32-4.41 (m, 1H), 3.78-3.93 (m, 2H), 3.31 (s, 3H), 2.95-3.09 (m, 3H), 2.78-2.90 (m, 3H).

* pure but unknown stereochemistry

Compound 191_E1: (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 539 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.22 (dt, J=5.58, 8.88 Hz, 1H), 6.99 (t, J=9.60 Hz, 1H), 6.63 (br d, J=3.51 Hz, 1H), 5.67-6.02 (m, 1H), 4.75 (d, J=2.64 Hz, 2H), 4.48-4.59 (m, 2H), 4.29-4.42 (m, 1H), 3.78-3.96 (m, 2H), 3.27-3.34 (m, 3H), 2.96-3.09 (m, 3H), 2.77-2.91 (m, 3H).

* pure but unknown stereochemistry

Compound 192_E1: (S*)-N-(5-chloro-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 505/507 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.19 (t, J=8.09 Hz, 1H), 6.95 (dd, J=8.60, 10.48 Hz, 1H), 6.55 (br d, J=2.51 Hz, 1H), 5.68-6.02 (m, 1H), 4.73 (d, J=1.88 Hz, 2H), 4.49-4.60 (m, 2H), 4.30-4.42 (m, 1H), 3.77-3.94 (m, 2H), 3.31 (s, 3H), 2.96-3.09 (m, 3H), 2.78-2.92 (m, 3H).

* pure but unknown stereochemistry

Compound 193_E1: (S*)-N-(5-bromo-2,4-difluorophenyl)-4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 549/551 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.33 (t, J=7.91 Hz, 1H), 6.94 (dd, J=7.91, 10.67 Hz, 1H), 6.54 (br d, J=2.51 Hz, 1H), 5.67-6.04 (m, 1H), 4.66-4.80 (m, 2H), 4.49-4.59 (m, 2H), 4.30-4.42 (m, 1H), 3.77-3.97 (m, 2H), 3.31 (s, 3H), 2.96-3.10 (m, 3H), 2.79-2.92 (m, 3H).

* pure but unknown stereochemistry

Compound 194_E1: (S*)-4-(((2,2-difluoroethyl)amino)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 521 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.64-7.71 (m, 1H), 7.59 (br dd, J=3.70, 8.47 Hz, 1H), 7.13 (t, J=9.35 Hz, 1H), 6.62 (s, 1H), 5.68-6.03 (m, 1H), 4.65-4.78 (m, 2H), 4.49-4.60 (m, 2H), 4.31-4.43 (m, 1H), 3.79-3.93 (m, 2H), 3.31 (s, 3H), 2.96-3.10 (m, 3H), 2.80-2.91 (m, 3H).

* pure but unknown stereochemistry

Compound 195: N10-(3-cyano-2,4-difluorophenyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide

Compound 195 was prepared in an analogous manner to 118.

LCMS [M+1]:460. ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.29 (dt, J=5.77, 9.10 Hz, 1H), 6.95-7.09 (m, 1H), 6.64 (br s, 1H), 6.09 (br d, J=3.76 Hz, 1H), 4.85-5.01 (m, 2H), 4.63-4.80 (m, 3H), 3.73-3.97 (m, 2H), 3.35 (s, 3H), 2.82-2.96 (m, 5H).

Compound 196: N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-[(2-oxopyrrolidin-1-yl) methyl]-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo [2,4-d] [1,2,5]oxadiazepine-10-carboxamide

Step 1. 4-[(4-chlorobutanoylamino)methyl]-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a mixture of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 80.00 mg, 189.20 nmol, 1.00 eq) and TEA (38.29 mg, 378.40 μmol, 52.45 μL 2.00 eq) in DCM (5.00 mL) was added 4-chlorobutanoyl chloride (26.68 mg, 189.20 μmol, 21.17 μL 1.00 eq), the mixture was stirred at 15° C. for 4 h. The residue was diluted with H₂O (10 mL) and extracted with DCM (10 mL*2). The combined organic layers were washed with brine (20 mL*2), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Dichloromethane:Methanol=10:1 Plate 1) to afford the title compound (60.00 mg, 113.77 μmol, 60.13% yield) as white solid. LCMS: 528 [M+1].

Step 2, N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4-[(2-oxopyrrolidin-1-yl) methyl]-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo [2,4-d] [1,2,5]oxadiazepine-10-carboxamide

To a solution of 4-[(4-chlorobutanoylamino)methyl]-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (40.00 mg, 75.85 μmol, 1.00 eq) in THF (4.00 mL) was added NaH (6.07 mg, 151.69 μmol, 60% purity, 2.00 eq) at 0° C. for 0.5 h, then the mixture was stirred at 15° C. for 1 h. The mixture was diluted with H₂O (10 mL) and extracted with EtOAc (10 mL*2). The combined organic layers were washed with brine (10 mL*2), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue combined with the reaction mixture of was purified by prep-HPLC(FA) to afford the title compound (13.00 mg, 25.16 μmol, 95% purity) as yellow solid,

LCMS: 491 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.58 (dd, J=2.64, 6.40 Hz, 1H), 7.16-7.24 (m, 1H), 7.02-7.10 (m, 1H), 6.56 (s, 1H), 4.70 (s, 3H), 4.40-4.55 (m, 2H), 3.79-3.94 (m, 2H), 3.74 (dd, J=7.40, 14.68 Hz, 1H), 3.35-3.46 (m, 2H), 3.31 (s, 3H), 3.23 (dt, J=5.65, 8.91 Hz, 1H), 2.80-2.91 (m, 2H), 2.36-2.48 (m, 2H), 1.89-2.07 (m, 2H).

Compound 204: N-(3-chloro-4-fluorophenyl)-4-((3,3-dimethylureido)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 40.00 mg, 94.60 μmol, 1.00 eq) and TEA (19.14 mg, 189.20 μmol, 26.23 μL 2.00 eq) in DCM (2.00 mL) was added N,N-dimethylcarbamoyl chloride (15.26 mg, 141.90 μmol, 13.04 μL 1.50 eq), then the mixture was stirred at 25° C. for 16 h. LCMS indicated that the starting material was consumed completely and desired product was detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (FA) to obtain the title compound (27.00 mg, 54.50 μmol, 57.61% yield, 99.7% purity) as white solid. LCMS: 494 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ=8.90 (s, 1H), 7.72 (dd, J=2.57, 6.85 Hz, 1H), 7.39-7.44 (m, 1H), 7.29 (t, J=9.11 Hz, 1H), 6.54 (t, J=5.14 Hz, 1H), 4.61 (s, 2H), 4.49-4.56 (m, 2H), 4.27-4.35 (m, 1H), 3.74 (br s, 2H), 3.22 (s, 3H), 3.11-3.18 (m, 1H), 3.11-3.18 (m, 1H), 3.11-3.18 (m, 1H), 2.79 (s, 6H), 2.72 (br t, J=5.38 Hz, 2H).

Compounds 197, 198, 200, 201, and 202 were prepared in an analogous manner to Compound 204.

Compound 197: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(propionamidomethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 479 [M+1]. ¹H NMR (400 MHz, DMSO-d6) δ=8.90 (s, 1H), 8.05 (t, J=5.75 Hz, 1H), 7.72 (dd, J=2.63, 6.91 Hz, 1H), 7.41 (ddd, J=2.75, 4.34, 9.05 Hz, 1H), 7.25-7.32 (m, 1H), 4.61 (s, 2H), 4.54-4.60 (m, 1H), 4.44-4.52 (m, 1H), 4.28 (dd, J=7.03, 14.24 Hz, 1H), 3.69-3.78 (m, 2H), 3.44 (br d, J=7.70 Hz, 1H), 3.16-3.23 (m, 4H), 2.72 (br t, J=5.69 Hz, 2H), 2.07-2.15 (m, 2H), 1.00 (t, J=7.58 Hz, 3H).

Compound 198: N-(3-chloro-4-fluorophenyl)-4-(cyclopropanecarboxamidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 491 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ=8.90 (s, 1H), 8.36 (br t, J=5.33 Hz, 1H), 7.73 (dd, J=2.57, 6.84 Hz, 1H), 7.42 (ddd, J=2.64, 4.27, 9.03 Hz, 1H), 7.26-7.32 (m, 1H), 4.62 (s, 2H), 4.54-4.61 (m, 1H), 4.45-4.53 (m, 1H), 4.28 (dd, J=7.22, 14.24 Hz, 1H), 3.68-3.81 (m, 2H), 3.44 (td, J=7.17, 14.40 Hz, 1H), 3.25 (br t, J=4.58 Hz, 1H), 3.21 (s, 3H), 2.72 (br t, J=5.58 Hz, 2H), 1.54-1.67 (m, 1H), 0.64-0.72 (m, 4H).

Compound 200: N-(3-chloro-4-fluorophenyl)-4-(isobutylaminomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 493 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ=8.90 (s, 1H), 8.02 (br t, J=5.50 Hz, 1H), 7.72 (dd, J=2.57, 6.85 Hz, 1H), 7.41 (ddd, J=2.63, 4.28, 8.99 Hz, 1H), 7.25-7.32 (m, 1H), 4.61 (s, 2H), 4.57 (dd, J=5.69, 14.12 Hz, 1H), 4.45-4.53 (m, 1H), 4.28 (dd, J=6.91, 14.12 Hz, 1H), 3.70-3.79 (m, 2H), 3.39-3.47 (m, 2H), 3.15-3.23 (m, 4H), 2.72 (br t, J=5.50 Hz, 2H), 2.39 (td, J=6.80, 13.66 Hz, 1H), 1.01 (dd, J=3.91, 6.85 Hz, 6H)

Compound 201: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-(pivalamidomethyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 507 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.58 (dd, J=2.57, 6.71 Hz, 1H), 7.29 (ddd, J=2.64, 4.17, 9.00 Hz, 1H), 7.10-7.16 (m, 1H), 4.71 (s, 2H), 4.52-4.65 (m, 2H), 4.36 (dd, J=5.71, 14.49 Hz, 1H), 3.74-3.90 (m, 2H), 3.54 (dd, J=7.22, 14.24 Hz, 1H), 3.33-3.37 (m, 1H), 3.28 (s, 3H), 2.83 (t, J=5.77 Hz, 2H), 1.18 (s, 9H).

Compound 202: ethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

LCMS: 495 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.56-7.61 (m, 1H), 7.56-7.61 (m, 1H), 7.58 (dd, J=2.64, 6.65 Hz, 1H), 7.56-7.61 (m, 1H), 7.29 (ddd, J=2.64, 4.05, 9.00 Hz, 1H), 7.10-7.16 (m, 1H), 4.72 (s, 2H), 4.53-4.61 (m, 2H), 4.31-4.39 (m, 1H), 4.10 (q, J=7.19 Hz, 2H), 3.75-3.88 (m, 1H), 3.75-3.88 (m, 1H), 3.37-3.44 (m, 1H), 3.29 (s, 4H), 2.82 (t, J=5.77 Hz, 2H), 1.20-1.29 (m, 3H)

Compound 203: cyclopropyl ((10-((3-chloro-4-fluorophenyl)carbamoyl-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

To a solution of cyclopropanol (100.00 mg, 1.72 mmol, 1.00 eq) and pyridine (408.16 mg, 5.16 mmol, 416.49 μL 3.00 eq) in DCM (5.00 mL) was added (4-nitrophenyl)carbonochloridate (346.68 mg, 1.72 mmol, 1.00 eq). The mixture was stirred at 20° C. for 1 h. TLC (PE:EtOAc=3:1) showed that reactant (4-nitrophenyl)carbonochloridate was consumed completely and one main new spot formed. The mixture was diluted with 10 mL of DCM and washed with HCl (1N, 30 mL*l), saturated NaHCO₃ solution (30 mL) and brine (20 mL*l). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum to give cyclopropyl (4-nitrophenyl)carbonate (400.00 mg, crude) as white solid and directly used in the next step.

Step 2. cyclopropyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

To a solution of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 35.00 mg, 82.77 μmol, 1.00 eq) and TEA (25.13 mg, 248.32 μmol, 34.42 μL 3.00 eq) in THF (1.00 mL) was added cyclopropyl (4-nitrophenyl) carbonate (36.95 mg, 165.54 μmol, 2.00 eq), then the mixture was stirred at 45° C. for 16 h. TLC (PE:EtOAc=0:1) showed that reactant cyclopropyl (4-nitrophenyl) carbonate was consumed completely and two new spots formed. The mixture combined with a pilot reaction (5 mg) was diluted with 15 mL of DCM and washed with water (10 mL*1) and brine (10 mL*1). Then the combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-TLC (PE:EtOAc=0:1), following by prep-HPLC (FA) to obtain the title compound (17.2 mg, 33.93 μmol, 37.59% yield, 95% purity) as white solid. LCMS: 507 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.58 (dd, J=2.64, 6.53 Hz, 1H), 7.17-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.51 (s, 1H), 4.92 (br s, 1H), 4.64-4.76 (m, 2H), 4.50-4.63 (m, 2H), 4.38 (br dd, J=4.20, 14.49 Hz, 1H), 4.09 (br d, J=3.89 Hz, 1H), 3.79-3.92 (m, 2H), 3.39-3.49 (m, 2H), 3.30 (s, 3H), 2.85 (t, J=5.77 Hz, 2H), 0.71 (br d, J=6.02 Hz, 4H).

Compound 199: N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4-((3,3,3-trifluoropropanamido)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 40.00 mg, 94.60 μmol, 1.00 eq) and 3,3,3-trifluoropropanoic acid (14.54 mg, 113.52 μmol, 10.03 μL 1.20 eq) in DMF (2.00 mL) was added HATU (43.16 mg, 113.52 μmol, 1.20 eq) and DIPEA (73.36 mg, 567.60 μmol, 99.14 μL 6.00 eq), then the mixture was stirred at 25° C. for 2 h. LCMS indicated that the starting material was consumed completely and desired product was detected. The mixture was diluted with 15 mL of DCM and washed with water (10 mL*l) and brine (10 mL*1). Then the combined organic phases were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC (FA) to get Compound 199(33.00 mg, 61.25 μmol, 64.74% yield, 98.9% purity) as white solid. LCMS: 533 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ=8.90 (s, 1H), 8.55 (br t, J=5.44 Hz, 1H), 7.72 (dd, J=2.57, 6.85 Hz, 1H), 7.38-7.45 (m, 1H), 7.25-7.32 (m, 1H), 4.57-4.66 (m, 3H), 4.47-4.55 (m, 1 H), 4.28 (dd, J=7.15, 14.37 Hz, 1H), 3.68-3.81 (m, 2H), 3.48 (td, J=7.11, 14.52 Hz, 1H), 3.25-3.31 (m, 3H), 3.20 (s, 3H), 2.72 (br t, J=5.50 Hz, 2H).

Compounds 205 and 206 were prepared in an analogous method to Compound 199.

Compound 205: N-(3-chloro-4-fluorophenyl)-4-((2-cyanoacetamido)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 490 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.58 (dd, J=2.64, 6.65 Hz, 1H), 7.29 (ddd, J=2.76, 4.11, 8.94 Hz, 1H), 7.08-7.18 (m, 1H), 4.72 (s, 2H), 4.50-4.67 (m, 3H), 4.33-4.44 (m, 1H), 3.74-3.91 (m, 2H), 3.63 (dd, J=7.09, 14.62 Hz, 1H), 3.36-3.56 (m, 2H), 3.29-3.30 (m, 1H), 3.29 (br s, 2H), 2.84 (t, J=5.71 Hz, 2H).

Compound 206: N-(3-chloro-4-fluorophenyl)-4-((2-hydroxyacetamido)methyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

LCMS: 481 [M+1]. ¹H NMR (400 MHz, METHANOL-d₄) δ=7.58 (dd, J=2.64, 6.65 Hz, 1H), 7.29 (ddd, J=2.64, 4.17, 9.00 Hz, 1H), 7.13 (t, J=8.97 Hz, 1H), 4.72 (s, 2H), 4.70-4.71 (m, 1H), 4.55-4.68 (m, 2H), 4.55-4.68 (m, 1H), 4.38 (dd, J=5.71, 14.24 Hz, 1H), 3.97-4.02 (m, 1H), 4.00 (s, 1H), 3.79-3.85 (m, 2H), 3.65 (dd, J=7.15, 14.18 Hz, 1H), 3.42 (dd, J=4.33, 14.24 Hz, 1H), 3.29 (br s, 2H), 3.29-3.30 (m, 1H), 2.83 (t, J=5.65 Hz, 2H).

Compound 207: 2,2,2-trifluoroethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

Step 1. 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113)

To a solution of 2,2,2-trifluoroethanol (100.00 mg, 999.60 μmol, 71.94 μL 1.00 eq) and pyridine (237.21 mg, 3.00 mmol, 242.05 μL 3.00 eq) in DCM (20.00 mL) was added phenyl carbonochloridate (156.51 mg, 999.60 μmol, 125.21 μL 1.00 eq). The mixture was stirred at 20° C. for 1 h. TLC (PE:EtOAc=3:1) showed that reactant phenyl carbonochloridate was consumed completely and one main new spot formed. The mixture was diluted with 10 mL of DCM and washed with HCl (1N, 30 mL*l) and brine (20 mL*l). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give phenyl 2,2,2-trifluoroethyl carbonate (250.00 mg, crude) as colorless oil.

Step 2. 2,2,2-trifluoroethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl)carbamate

To a solution of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 35.00 mg, 82.77 μmol, 1.00 eq) and TEA (25.13 mg, 248.31 μmol, 34.42 μL 3.00 eq) in THF (2.00 mL) was added phenyl 2,2,2-trifluoroethyl carbonate (54.67 mg, 248.31 μmol, 3.00 eq), then the mixture was stirred at 45° C. for 16 h. LCMS indicated that reactant phenyl 2,2,2-trifluoroethyl carbonate was consumed completely and desired product was detected. The mixture combined with a pilot reaction (5 mg) was concentrated in vacuum. The residue was purified by prep-HPLC (TFA), following by prep-TLC (PE:EtOAc=0:1) and prep-HPLC (FA) to obtain the title compound (6.5 mg, 11.84 μmol, 12.30% yield, 98% purity) white solid. LCMS: 549 [M+1]. ¹H NMR (400 MHz, CHLOROFORM-d) δ=7.57 (dd, J=2.70, 6.46 Hz, 1H), 7.17-7.23 (m, 1H), 7.03-7.10 (m, 1H), 6.50 (s, 1H), 5.22 (br s, 1H), 4.64-4.76 (m, 2H), 4.36-4.63 (m, 5H), 3.80-3.92 (m, 2H), 3.42-3.55 (m, 2H), 3.30 (s, 3H), 2.85 (t, J=5.58 Hz, 2H).

Compound 208: N-(3-chloro-4-fluorophenyl)-4-(ethylsulfonamidomethyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide (Compound 113, 40.00 mg, 94.60 μmol, 1.00 eq) and TEA (19.14 mg, 189.20 μmol, 26.23 μL 2.00 eq) in DCM (2.00 mL) was added ethanesulfonyl chloride (18.25 mg, 141.90 μmol, 13.42 μL 1.50 eq), then the mixture was stirred at 25° C. for 16 h. LCMS indicated that the starting material was consumed completely and desired product was detected. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC to obtain the title compound (25.00 mg, 46.61 μmol, 49.27% yield, 96% purity) as white solid. LCMS: 515 [M+1]. ¹H NMR (400 MHz, DMSO-d₆) δ=8.91 (s, 1H), 7.72 (dd, J=2.57, 6.84 Hz, 1H), 7.38-7.49 (m, 2H), 7.25-7.32 (m, 1H), 4.57-4.65 (m, 3H), 4.50 (quin, J=6.31 Hz, 1H), 4.28 (dd, J=7.22, 14.37 Hz, 1H), 3.67-3.80 (m, 2H), 3.24 (s, 3H), 3.20 (br s, 2H), 3.07 (q, J=7.28 Hz, 2H), 2.72 (br t, J=5.58 Hz, 2H), 1.20 (t, J=7.34 Hz, 3H), 1.16-1.24 (m, 1H).

Compounds 129 and 130 were prepared in an analogous method to Compound 208.

Compound 209: N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-4,5,8,9,10,11-hexahydro-[1,2,5]oxadiazepino[5,4-b]indazole-10-carboxamide

Step 1. ethyl 3-(2-tert-butoxy-2-oxo-acetyl)-4-oxo-cyclohexane carboxylate

To a solution of LiHMDS (1 M, 35.26 mL, 1.20 eq) in THF (30.00 mL) was added ethyl 4-oxocyclohexanecarboxylate (5.00 g, 29.38 mmol, 4.67 mL, 1.00 eq) drop-wise at −65° C., after stirring for 30 min, ditert-butyl oxalate (6.54 g, 32.32 mmol, 1.10 eq) in THF (10.00 mL) was added at −65° C., the mixture was slowly warmed to 20° C. and stirred at 20° C. for 1 hr. TLC showed the reaction was completed. The mixture was poured into HCl (0.5 N, 200 mL), extracted with ethyl acetate (80 mL*3). The combined organic layer was washed with saturate NaHCO₃ aqueous (100 mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum to afford the title compound (6.90 g, 23.13 mmol, 78.73% yield) which was used for the next step without further purification.

Step 2. 3-tert-butyl 5-ethyl 4,5,6,7-tetrahydro-2H-indazole-3,5-dicarboxylate

To a solution of ethyl 3-(2-tert-butoxy-2-oxo-acetyl)-4-oxo-cyclohexanecarboxylate (6.70 g, 22.46 mmol, 1.00 eq) in EtOH (70.00 mL) was added N₂H₄.H₂O (1.32 g, 22.46 mmol, 1.28 mL, 1.00 eq). The mixture was stirred at 20° C. for 2 hr. TLC showed the reaction was completed. The mixture concentrated in vacuum, the residue was poured into aqueous HCl (0.5 N, 50 mL), extracted with ethyl acetate (100 mL*2). The organic layer was washed with brine (50 mL), and dried over anhydrous Na₂SO₄ and concentrated in vacuum. The crude was purified by column chromatography to afford the title compound (4.70 g, 15.17 mmol, 67.54% yield, 95% purity) as colorless oil.

Step 3, 3-tert-butoxycarbonyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid

To a solution of 3-tert-butyl 5-ethyl 4,5,6,7-tetrahydro-2H-indazole-3,5-dicarboxylate (2.40 g, 8.15 mmol, 1.00 eq) in MeOH (20.00 mL), THF (20.00 mL) and H₂O (10.00 mL) was added LiOH.H₂O (1.50 g, 35.75 mmol, 4.39 eq) at 10° C. with ice-water bath. The mixture was stirred at 20° C. for 3 hr. TLC showed the reactant was consumed and a major spot detected. The mixture was concentrated in vacuum, the residue was acidified by 1 N HCl to pH=5, and filtered to give the title compound (1.60 g, 5.41 mmol, 66.35% yield, 90% purity) as white solid

Step 4. tert-butyl 5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate

To a solution of 3-tert-butoxycarbonyl-4,5,6,7-tetrahydro-2H-indazole-5-carboxylic acid (1.50 g, 5.63 mmol, 1.00 eq) and 3-chloro-4-fluoro-aniline (983.92 mg, 6.76 mmol, 1.20 eq) in DMF (5.00 mL) was added DIPEA (2.18 g, 16.90 mmol, 2.95 mL, 3.00 eq) and HATU (2.36 g, 6.20 mmol, 1.10 eq). The mixture was stirred at 20° C. for 16 hr. LCMS showed the reactant consumed, and 45% desired product and multiple peaks detected. The mixture was poured into water (200 mL), extracted with ethyl acetate (100 mL*3). The combined organic layer was washed with brine (50 mL*2), dried over anhydrous Na₂SO₄ and concentrated in vacuum. The crude was purified by reversed-phase flash separation to afford the title compound (650.00 mg, 1.65 mmol, 29.26% yield, 99.8% purity) as white solid.

Step 5, 5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid

To a solution of tert-butyl 5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylate (300.00 mg, 761.73 μmol, 1.00 eq) in DCM (6.00 mL) was added TFA (4.27 g, 37.41 mmol, 2.77 mL, 49.11 eq) at 10° C. with ice-water bath. The mixture was stirred at 20° C. for 3 hr. TLC and LCMS showed the reactant was consumed and a major spot detected. The mixture was concentrated in vacuum to afford the title compound (250.00 mg, 740.24 μmol, 97.18% yield) as white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 7.96 (dd, J=2.64, 6.90 Hz, 1H), 7.49 (ddd, J=2.57, 4.30, 9.07 Hz, 1H), 7.31-7.41 (m, 1H), 3.02 (d, J=11.54 Hz, 1H), 2.57-2.83 (m, 5H), 2.09 (d, J=10.16 Hz, 1H), 1.65-1.86 (m, 1H).

Step 6. N5-(3-chloro-4-fluoro-phenyl)-N3-hydroxy-N3-methyl-4,5,6,7-tetrahydro-2H-indazole-3,5-dicarboxamide

To a solution of 5-[(3-chloro-4-fluoro-phenyl)carbamoyl]-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid (100.00 mg, 296.09 μmol, 1.00 eq) and N-methylhydroxylamine (74.19 mg, 888.28 μmol, 3.00 eq, HCl) in DMF (2.00 mL) was added HATU (135.10 mg, 355.31 μmol, 1.20 eq) and DIPEA (191.34 mg, 1.48 mmol, 258.56 μL 5.00 eq). The mixture was stirred at 20° C. for 16 hr. LCMS showed the reaction was completed. The reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to afford the title compound (90.00 mg, 223.30 μmol, 75.42% yield, 91% purity) as yellow solid. LCMS: 367/369 [M+1].

Step 7, N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-4,5,8,9,10,11-hexahydro-[1,2,5]oxadiazepino[5,4-b]indazole-10-carboxamide

To a solution of N5-(3-chloro-4-fluoro-phenyl)-N3-hydroxy-N3-methyl-4,5,6,7-tetrahydro-2H-indazole-3,5-dicarboxamide (50.00 mg, 136.33 μmol, 1.00 eq) and 3-bromooxetane (37.35 mg, 272.65 μmol, 2.00 eq) in DMF (2.00 mL) was added Cs₂CO₃ (66.63 mg, 204.49 μmol, 1.50 eq) and TBAI (5.04 mg, 13.63 μmol, 0.10 eq). The mixture was stirred at 80° C. for 7.5 hr. LCMS showed the reactant consumed and the major desired product detected. The mixture was poured into water (20 mL), extracted with ethyl acetate (10 mL*3), the organic layer was washed with brine (20 mL), dried over anhydrous Na₂SO₄ and concentrated in vacuum. The crude was purified by prep-HPLC to afford N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-4,5,8,9,10,11-hexahydro-[1,2,5]oxadiazepino[5,4-b]indazole-10-carboxamide (45.00 mg, 101.10 μmol, 74.16% yield, 95% purity) as white solid. LCMS: 423/425 [M+1], 1H NMR (400 MHz, CHLOROFORM-d) δ 7.74 (dd, J=2.26, 6.53 Hz, 1H), 7.56 (br d, J=10.04 Hz, 1H), 7.34 (td, J=2.13, 4.77 Hz, 1H), 7.08 (dt, J=1.19, 8.75 Hz, 1H), 4.45-4.63 (m, 2H), 4.34-4.43 (m, 1 H), 3.63-3.88 (m, 2H), 3.31 (d, J=1.25 Hz, 3H), 3.10-3.25 (m, 1H), 2.82-3.04 (m, 2H), 2.40-2.71 (m, 3H), 2.26 (br d, J=13.05 Hz, 1H), 1.94-2.09.

Compound 210: (4S,9R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-4-((2,2,2-trifluoroethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][b 1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-Butyl (5R)-5,13-dimethyl-14-oxo-11-(2,2,2-trifluoroethoxymethyl)-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate

NaH (10.04 mg, 251.08 μmol, 22.70 μL, 60% purity, 1.0 eq) was added to a solution of tert-butyl (5R)-11-(hydroxymethyl)-5,13-dimethyl-14-oxo-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate (100.00 mg, 251.08 μmol, 1.00 eq) in THF (1.00 mL) with stirring at −10° C. for 0.5 h under N₂ Then a solution of 2,2,2-trifluoroethyl trifluoromethanesulfonate (233.11 mg, 1.00 mmol, 35.39 μL, 4 eq) in THF (0.5 mL) was added into the mixture. The mixture was stirred at 0° C. for 2 h. The mixture was cooled to −10° C., and NaH (10.04 mg, 251.08 μmol, 60% purity, 1.0 eq) was added, and the mixture was stirred for 30 min, followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (233.11 mg, 1.00 mmol, 4 eq) was added. The mixture was stirred at 0° C. for 1 h. The mixture was poured into 10 mL of ice aqueous 1N HCl solution and extracted with EtOAc (15 mL*3). The organic layers were combined and dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue. The residue was purified by prep-TLC (Ethyl acetate:Petroleum ether=1:3) to give the title compound (30 mg, 26.64% yield) as colorless oil and by-product tert-butyl (5R)-5,13-dimethyl-11-methylene-14-oxo-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate (45 mg, 51.44% yield) as colorless oil.

Step 2. (5R)-5,13-Dimethyl-11-(2,2,2-trifluoroethoxymethyl)-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-dien-14-one

To a solution of tert-butyl (5R)-5,13-dimethyl-14-oxo-11-(2,2,2-trifluoroethoxymethyl)-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate (58 mg, 129.34 μmol, 1 eq) in DCM (3 mL) was added TFA (462.00 mg, 4.05 mmol, 0.3 mL, 31.33 eq), then the mixture was stirred at 15° C. for 1 h. The mixture was directly concentrated in vacuo to afford the title compound (60 mg, crude, TFA) as yellow oil, which was directly used in the next step.

Step 3, (4S,9R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-4-((2,2,2-trifluoroethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of (5R)-5,13-dimethyl-11-(2,2,2-trifluoroethoxymethyl)-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-dien-14-one (60 mg, 129.77 μmol, 1 eq, TFA) in DCM (7 mL) was added TEA (78.79 mg, 778.64 μmol, 108.38 μL, 6 eq) and (5R)-5,13-dimethyl-11-(2,2,2-trifluoroethoxymethyl)-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-dien-14-one (60 mg, 129.77 μmol, 1 eq, TFA), then the mixture was stirred at 15° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to obtain the title compound (43 mg, 84.24 μmol, 64.91% yield, 100% purity) as white solid. LCMS: 511[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.78 (dd, J=2.82, 5.46 Hz, 1H), 7.58 (m, 1H), 7.11-7.18 (m, 1H), 6.54 (s, 1H), 5.13 (m, 1H), 4.84 (d, J=15.69 Hz, 1H), 4.63-4.69 (m, 1H), 4.55-4.62 (m, 1H), 4.50 (d, J=15.56 Hz, 1H), 4.39-4.46 (m, 1H), 3.88-3.97 (m, 2H), 3.73-3.87 (m, 2H), 3.31 (s, 3H), 3.05 (dd, J=5.83, 16.00 Hz, 1H), 2.70 (d, J=15.94 Hz, 1H), 1.20 (d, J=6.90 Hz, 3H).

Compound 211: (S*)-N-(3-cyano-4-fluorophenyl)-2-methyl-1-oxo-4-((2,2,2-trifluoroethoxy)methyl)-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-Butyl 4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate

To a suspension of NaH (85.13 mg, 2.13 mmol, 60% purity, 2.5 eq) in DMF (3 mL) was added a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (single enantiomer, 300 mg, 851.34 μmol, 1 eq) in DMF (0.5 mL) at −40° C. dropwise under N₂. The mixture was stirred at −40° C. for 0.5 hr. 2,2-difluoroethyl trifluoromethanesulfonate (546.85 mg, 2.55 mmol, 3 eq) was added at −40° C. The reaction mixture was stirred at −20° C. for 1 hr. The reaction mixture was quenched with 1N HCl (30 mL) at 0° C. and extracted with EA (30 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was combined with another batch to purify by column chromatography (SiO₂, PE:EA:3:1-1:1) to give 400 mg of the title compound as a white solid.

Step 2, 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

To a solution of tert-butyl 4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (160 mg, 384.23 μmol, 1 eq) in DCM (4 mL) was added TFA (6.16 g, 54.02 mmol, 4.00 mL, 140.60 eq). The mixture was stirred at 20° C. for 30 min. TLC (DCM:MeOH=10:1) showed starting material was consumed. The mixture was concentrated in vacuo to give the title compound (180 mg, crude, TFA) as brown oil.

Step 3. (S*)N-(3-cyano-4-fluoro-phenyl)-4-(2,2-difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide

To a mixture of 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (84 mg, 195.20 μmol, 1 eq, TFA) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (50.02 mg, 195.20 μmol, 1 eq) in DCM (5 mL) was added TEA (98.76 mg, 976.00 μmol, 135.85 μL, 5 eq). The mixture was stirred at 20° C. for 2 h. LCMS showed one main peak with desired MS was detected. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC(FA) to give the title compound (45.93 mg, 94.72 μmol, 48.52% yield, 98.66% purity) as white solid. LCMS: 479 [M+1], 1H NMR (400 MHz, CDCl₃) δ=7.69 (dd, J=2.75, 5.44 Hz, 1H), 7.52 (ddd, J=2.81, 4.58, 9.11 Hz, 1H), 7.06 (t, J=8.68 Hz, 1H), 6.67 (s, 1H), 5.68-5.98 (m, 1H), 4.56 (quin, J=5.72 Hz, 1H), 4.45-4.52 (m, 1H), 4.30-4.37 (m, 1H), 3.75-3.84 (m, 2H), 3.60-3.74 (m, 4H), 3.23 (s, 3H), 2.79 (t, J=5.81 Hz, 2H).

Compound 212: (S*)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

The title compound was prepared in a manner analogous to Compound 211 using 4-(2,2-difluoroethoxymethyl)-2-methyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one and phenyl (4-fluoro-3-(trifluoromethyl)phenyl)carbamate in step 3. LCMS: 522 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.68 (dd, J=2.75, 6.17 Hz, 1H), 7.57-7.63 (m, 1H), 7.15 (t, J=9.35 Hz, 1H), 6.68 (s, 1H), 5.75-6.09 (m, 1H), 4.73 (s, 2H), 4.54-4.68 (m, 2H), 4.38-4.46 (m, 1H), 3.84-3.96 (m, 2H), 3.69-3.83 (m, 4H), 3.32 (s, 3H), 2.88 (t, J=5.75 Hz, 2H).

*Pure but unknown enantiomer.

Compound 213: (R)—N-(3-cyano-4-fluorophenyl)-2,4,4,9-tetramethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

Step 1. tert-Butyl N-hydroxy-N-methyl-carbamate

To a solution of N-methylhydroxylamine (20 g, 425.02 mmol, 1 eq, HCl) and NaHCO₃ (53.56 g, 637.53 mmol, 24.80 mL, 1.5 eq) in THF (400 mL) and H₂O (200 mL) was added a solution Boc₂O (92.76 g, 425.02 mmol, 97.64 mL, 1 eq) in THF (100 mL) at 0° C. slowly. Then the mixture was stirred at 16° C. for 16 hr. The mixture was diluted with H₂O (200 mL) and extracted with EtOAc (200 mL*3). Then the organic layer was extracted with 1N HCl (200 mL). The combined organic layered were dried over MgSO₄, filtered and concentrated under reduced pressure to give the title compound (29.6 g, crude) as red liquid.

Step 2. Methyl 2-[tert-butoxycarbonyl(methyl)amino]oxy-2-methyl-propanoate

To a solution of tert-butyl N-hydroxy-N-methyl-carbamate (5 g, 33.97 mmol, 1 eq) in MeOH (50 mL) was added CH₃ONa (1.84 g, 33.97 mmol, 1 eq) and methyl 2-bromo-2-methyl-propanoate (6.15 g, 33.97 mmol, 4.39 mL, 1 eq) at 0° C. Then the mixture was heated to 60° C. with stirring for 16 h. Then to the mixture was added another batch of CH₃ONa (0.92 g, 17 mmol, 0.5 eq) and methyl 2-bromo-2-methylpropanoate (3.08 g, 17 mmol, 2.2 mL, 0.5 eq). The mixture was stirred at 60° C. for 5 hr. The mixture was concentrated under reduced pressure. The residue was dissolved with H₂O (80 mL) and extracted with EA (80 mL*3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 20/1) to afford the title compound (8.05 g, crude) as white liquid.

Step 3. tert-Butyl N-(2-hydroxy-1,1-dimethyl-ethoxy)-N-methyl-carbamate

To a suspension of LiBH₄ (1.42 g, 65.11 mmol, 2 eq) in THF (80 mL) was added a solution of methyl 2-[tert-butoxycarbonyl(methyl)amino]oxy-2-methyl-propanoate (8.05 g, 32.55 mmol, 1 eq) in THF (20 mL) at −40° C. under N2. Then the mixture was stirred at 0° C. for 4 hr. The reaction was poured into sat. aq. NH₄Cl (200 mL) and extracted with EtOAc (150 mL*3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified via column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/1 to 20/1) to give the title compound (3.8 g, 17.33 mmol, 53.24% yield) as white liquid and impure product with 80% purity (2.4 g, 8.76 mmol) as white liquid.

Step 4, 2-Methyl-2-(methylaminooxy)propan-1-ol

To a solution of tert-butyl N-(2-hydroxy-1, l-dimethyl-ethoxy)-N-methyl-carbamate (3.8 g, 17.33 mmol, 1 eq) in dioxane (10 mL) was added HCl/dioxane (4 M, 6 mL, 1.38 eq). The mixture was stirred at 16° C. for 2 hr. The mixture was concentrated under reduced pressure to give the title compound (3.04 g, crude, HCl) as light yellow oil, used in the next step directly.

Step 5. tert-Butyl (6R)-3-[(2-hydroxy-1,1-dimethyl-ethoxy)-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of (6R)-5-tert-butoxycarbonyl-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (800 mg, 2.84 mmol, 1 eq) and 2-methyl-2-(methylaminooxy)propan-1-ol (575.34 mg, 3.70 mmol, 1.3 eq, HCl) in pyridine (5 mL) was added EDCI (708.73 mg, 3.70 mmol, 1.3 eq). The mixture was stirred at 30° C. for 16 hr. The mixture was combined with another batch and was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL*3). The combined organic layers were washed with 1N HCl (100 mL*2), dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 1/5) to give the title compound (918 mg) as light yellow solid.

Step 6. tert-Butyl (R)-6-methyl-3-(methyl((2-methyl-1-((methylsulfonyl)oxy)propan-2-yl)oxy)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl (R)-6-methyl-3-(methyl((2-methyl-1-((methylsulfonyl)oxy)propan-2-yl)oxy)carbamoyl)-2-(methylsulfonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl (6R)-3-[(2-hydroxy-1,1-dimethyl-ethoxy)-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (600 mg, 1.57 mmol, 1 eq) in DCM (10 mL) was added DIEA (608.27 mg, 4.71 mmol, 819.78 μL, 3 eq) and MsCl (215.65 mg, 1.88 mmol, 145.71 μL, 1.2 eq) at 0° C. The mixture was stirred at 0° C. for 2 h. Additional MsCl (215.65 mg, 1.88 mmol, 145.71 μL, 1.2 eq) was added and the mixture was stirred at 0° C. for 0.5 hr. The mixture was diluted with H₂O (20 mL) and extracted with DCM (20 mL). The organic layer was washed with 0.5N HCl (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuum to give a mixture (900 mg crude) of tert-butyl (R)-6-methyl-3-(methyl((2-methyl-1-((methylsulfonyl)oxy)propan-2-yl)oxy)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl (R)-6-methyl-3-(methyl((2-methyl-1-((methylsulfonyl)oxy)propan-2-yl)oxy)carbamoyl)-2-(methylsulfonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate as white solid, used in the next step directly.

Step 7. tert-Butyl (5R)-5,11,11,13-tetramethyl-14-oxo-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate

To a mixture of tert-butyl (R)-6-methyl-3-(methyl((2-methyl-1-((methylsulfonyl)oxy)propan-2-yl)oxy)carbamoyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate and tert-butyl (R)-6-methyl-3-(methyl((2-methyl-1-((methylsulfonyl)oxy)propan-2-yl)oxy)carbamoyl)-2-(methylsulfonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (820 mg crude) in THF (15 mL) was added NaH (164.00 mg, 4.10 mmol, 60% purity, 2.5 eq) at 0° C. The mixture was heated to 45° C. with stirring for 14 hr. The mixture was poured into aqueous 1N HCl (40 mL) solution and extracted with EtOAc (20 mL*3). The combined organic layers were washed with aqueous saturated NaHCO₃ solution (40 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=30/l to 1:1) to give the title compound (440 mg, 1.15 mmol, 70.16% yield, 95.3% purity) as white solid.

Step 8. (5R)-5,11,11,13-Tetramethyl-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-dien-14-one

To a solution of tert-butyl (5R)-5,11,11,13-tetramethyl-14-oxo-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxylate (150 mg, 411.59 μmol, 1 eq) in DCM (5 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 16.41 eq). The mixture was stirred at 16° C. for 2 hr. The mixture was concentrated under reduced pressure to give the title compound (164 mg, crude, TFA) yellow oil. The crude title compound was not purified and used in the next step directly.

Step 9. (R)—N-(3-Cyano-4-fluorophenyl)-2,4,4,9-tetramethyl-1-oxo-1,4,5,8,9,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide

To a solution of (5R)-5,11,11,13-tetramethyl-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-dien-14-one (82 mg, 216.73 μmol, 1 eq, TFA) in DCM (2 mL) was added TEA (109.66 mg, 1.08 mmol, 150.83 μL, 5 eq) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (55.53 mg, 216.73 μmol, 1 eq). The mixture was stirred at 16° C. for 16 hr. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give the title compound (54.35 mg, 127.32 μmol, 58.75% yield, 99.9% purity) as white solid. LCMS: 427 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.79 (dd, J=2.8, 5.2 Hz, 1H), 7.57-7.58 (m, 1H), 7.15 (t, J=8.4 Hz, 1H), 6.53 (s, 1H), 5.11-5.17 (m, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.51 (d, J=15.2 Hz, 1H), 4.25 (s, 2H), 3.29 (s, 3H), 3.05 (dd, J=2.0, 15.6 Hz, 1H), 2.70 (d, J=15.6 Hz, 1H), 1.38 (d, J=17.6 Hz, 6H), 1.19 (d, J=6.8 Hz, 3H).

Compound 214: (5R)—N-[4-Fluoro-3-(trifluoromethyl)phenyl]-5,11,11,13-tetramethyl-14-oxo-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-diene-4-carboxamide

To a solution of (5R)-5,11,11,13-tetramethyl-12-oxa-4,8,9,13-tetrazatricyclo[7.5.0.0^(2,7)]tetradeca-1,7-dien-14-one (82 mg, 216.73 μmol, 1 eq, TFA) in DCM (2 mL) was added TEA (131.59 mg, 1.30 mmol, 181.00 μL, 6 eq) and phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (64.85 mg, 216.73 μmol, 1 eq). The mixture was stirred at 16° C. for 16 hr. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA) to give the title compound (46.1 mg, 98.01 μmol, 45.22% yield, 99.8% purity) as white solid. LCMS: 470 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.68 (dd, J=2.8, 6.0 Hz, 1H), 7.57-7.60 (m, 1H), 7.14 (t, J=9.2 Hz, 1H), 6.53 (s, 1H), 5.12-5.18 (m, 1H), 4.83 (d, J=15.2 Hz, 1H), 4.51 (d, J=15.2 Hz, 1H), 4.25 (s, 2H), 3.28 (s, 3H), 3.05 (dd, J=5.6, 16.0 Hz, 1H), 2.70 (d, J=16.0 Hz, 1H), 1.38 (d, J=17.6 Hz, 6H), 1.19 (d, J=6.8 Hz, 3H).

Compound 215: (4S,9R)-4-(Hydroxymethyl)-10-(4-iodobenzoyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one

Step 1. (4S,9R)-4-(Hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one

A mixture of tert-butyl (4S,9R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxylate (120 mg, 327.50 μmol, 1 eq), and TFA (3.08 g, 27.01 mmol, 2.00 mL, 82.48 eq) in DCM (4 mL) was stirred at 15° C. for 1 hr under N₂ atmosphere. The mixture was concentrated in vacuum to give the title compound (124 mg, 326.04 μmol, 99.55% yield, TFA) as a yellow oil, which was used directly in next step.

Step 2. (4S,9R)-4-(Hydroxymethyl)-10-(4-iodobenzoyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-1(2H)-one

A mixture of (4S,9R)-4-(hydroxymethyl)-2,9-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepin-1-one (124 mg, 326.04 μmol, 1 eq, TFA), 4-iodobenzoyl chloride (104.25 mg, 391.25 μmol, 1.2 eq), TEA (98.98 mg, 978.13 μmol, 136.14 μL, 3 eq), and DMAP (3.98 mg, 32.60 μmol, 0.1 eq) in DCM (5 mL) was degassed and purged with N₂ for 3 times. The mixture was stirred at 15° C. for 16 hr under N₂ atmosphere. The mixture was concentrated in vacuum. The residue was purified by Prep-HPLC to give the title compound (150.08 mg, 281.23 μmol, 86.26% yield, 93% purity) as a white solid. LCMS: 497 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ 7.78 (br d, J=7.53 Hz, 2H), 7.17 (d, J=7.91 Hz, 2H), 5.36-5.71 (m, 1H), 4.18-4.81 (m, 5H), 3.63-3.92 (m, 2H), 3.29 (br s, 4H), 2.50-2.77 (m, 1H), 1.84-2.28 (m, 1H), 1.25 (br s, 2H), 1.09-1.37 (m, 1H).

Compound 216: N-(3-Chloro-4-fluoro-phenyl)-2-methyl-1-oxo-3,4,5,8,9,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl N-(benzyloxy carbonylamino)-N-methyl-carbamate

To a solution of tert-butyl N-amino-N-methyl-carbamate (3.00 g, 20.52 mmol, 1.00 eq) in dioxane (20.00 mL) was added a solution of NaOH (820.80 mg, 20.52 mmol, 1.00 eq) in H₂O (5.00 mL), followed by CbzCl (4.55 g, 26.68 mmol, 3.79 mL, 1.30 eq), the reaction mixture was stirred at 25° C. for one hour. The reaction mixture was diluted with EA (200 mL) and washed with water (80 mL×3), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound (4.00 g, 14.27 mmol, 69.54% yield) was obtained as yellow oil. LCMS: 303 [M+23].

Step 2. Methyl 2-[benzyloxycarbonyl-[tert-butoxycarbonyl (methyl)amino]amino]acetate

To a mixture of tert-butyl N-(benzyloxycarbonylamino)-N-methyl-carbamate (4.00 g, 14.27 mmol, 1.00 eq) and methyl 2-bromoacetate (3.27 g, 21.41 mmol, 2.02 mL, 1.50 eq) in DMF (10.00 mL) was added K₂CO₃ (2.96 g, 21.41 mmol, 1.50 eq) under N₂, the reaction mixture was stirred at 50° C. for 16 hours. The reaction mixture was diluted with EA (150 mL) and washed with water (50 mL×3), the organic phase was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound (3.50 g, 9.93 mmol, 69.60% yield) as yellow oil. LCMS: 375 [M+23].

Step 3, tert-Butyl N-[benzyloxycarbonyl(2-hydroxyethyl)amino]-N-methyl-carbamate

To a solution of methyl 2-[benzyloxycarbonyl-[tert-butoxycarbonyl(methyl)amino] amino]acetate (3.50 g, 9.93 mmol, 1.00 eq) in THF (30.00 mL) was added LiBH₄ (432.55 mg, 19.86 mmol, 2.00 eq) under N₂ at 0° C., the reaction mixture was stirred at 20° C. for 2 hours The reaction was quenched with water (150 mL) and then extracted with EA (200 mL×3), the combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound (2.40 g, 7.40 mmol, 74.51% yield) was obtained as yellow oil. LCMS: 347 [M+23].

Step 4. Benzyl N-(2-hydroxyethyl-N-(methylamino) carbamate

To a solution of tert-butyl N-[benzyloxycarbonyl(2-hydroxyethyl)amino]-N-methyl-carbamate (2.40 g, 7.40 mmol, 1.00 eq) in dioxane (20.00 mL) was added HCl/dioxane (4 M, 20.00 mL, 10.81 eq), the reaction mixture was stirred at 25° C. for one hour. Organics were removed under reduced pressure to afford the title compound (1.80 g, crude, HCl) as yellow oil. The crude product was used in next step directly without purification.

Step 5. tert-Butyl 3-[[benzyloxycarbonyl(2-hydroxyethyl)amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (1.50 g, 5.61 mmol, 1.00 eq) and benzyl N-(2-hydroxyethyl)-N-(methylamino)carbamate (1.76 g, 6.73 mmol, 1.20 eq, HCl) in DMF (20.00 mL) were added PYBOP (3.50 g, 6.73 mmol, 1.20 eq), HOBt (909.97 mg, 6.73 mmol, 1.20 eq) and DIPEA (2.90 g, 22.45 mmol, 3.92 mL, 4.00 eq), the reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was diluted with EA (200 mL) and washed with water (100 mL×3), the organic layer was dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography. Further purification by prep-HPLC (FA) afforded the title compound (1.50 g, 2.53 mmol, 45.17% yield, 80% purity) as yellow solid.

LCMS: 474 [M+1].

Step 6, tert-Butyl 3-[[benzyloxycarbonyl (2-methylsulfonyloxyethyl)amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl 3-[[benzyloxycarbonyl(2-hydroxyethyl)amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (500.00 mg, 1.06 mmol, 1.00 eq) and TEA (214.52 mg, 2.12 mmol, 293.86 μL, 2.00 eq) in DCM (10.00 mL) was added MsCl (242.85 mg, 2.12 mmol, 164.09 μL, 2.00 eq) under N₂ at 0° C., the reaction mixture was stirred at 20° C. for 30 minutes. The reaction was quenched with water (30 mL) and then extracted with DCM (80 mL×2), the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give the title compound (380.00 mg, 661.34 μmol, 62.39% yield, 96% purity) as white solid. LCMS: 552 [M+1].

Step 7. O₃-benzyl O₁₀-tert-butyl 2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepine-3,10-dicarboxylate

To a solution of tert-butyl 3-[[benzyloxycarbonyl(2-methylsulfonyloxyethyl)amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (380.00 mg, 688.89 μmol, 1.00 eq) in THF (15.00 mL) was added NaH (55.11 mg, 1.38 mmol, 60% purity, 2.00 eq) under N₂ at −10° C., the reaction mixture was stirred at 25° C. for 16 hours. The reaction was quenched with water (20 mL) and then extracted with EA (50 mL×3), the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography to afford the title compound (130.00 mg, 285.39 μmol, 41.43% yield) as white solid. LCMS: 456 [M+1].

Step 8, tert-Butyl 2-methyl-1-oxo-3,4,5,8,9,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepine-10-carboxylate

To a solution of O₃-benzyl O₁₀-tert-butyl 2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepine-3,10-dicarboxylate (250.00 mg, 548.84 μmol, 1.00 eq) in MeOH (15.00 mL) was added Pd/C (50.00 mg, 10% purity) under N₂, the suspension was degassed under vacuum and purged with H₂ three times, the mixture was stirred under H₂ (15 psi) at 25° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (145.00 mg, crude) as yellow oil. The crude product was used in the next step directly without purification. LCMS: 322 [M+1].

Step 9, 2-Methyl-4,5,8,9,10,11-hexahydro-3H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepin-1-one

To a solution of tert-butyl 2-methyl-1-oxo-3,4,5,8,9,11-hexahydropyrido[2,3]pyrazolo [2,4-c][1,2,5]triazepine-10-carboxylate (15.00 mg, 46.67 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (384.97 mg, 3.38 mmol, 249.98 μL, 72.34 eq), the reaction mixture was stirred at 25° C. for one hour. Solvent was removed under reduced pressure. The title compound (15.00 mg, crude, TFA) was obtained as yellow oil. The crude product was used in next step directly without purification.

Step 10. N-(3-Chloro-4-fluoro-phenyl)-2-methyl-1-oxo-3,4,5,8,9,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepine-10-carboxamide

To a mixture of 2-methyl-4,5,8,9,10,11-hexahydro-3H-pyrido[2,3]pyrazolo[2,4-c] [1,2,5]triazepin-1-one (15.00 mg, 44.74 μmol, 1.00 eq, TFA) in DCM (2.00 mL) was added TEA (18.11 mg, 178.95 μmol, 24.81 μL, 4.00 eq), followed by phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (11.89 mg, 44.74 μmol, 1.00 eq), the reaction mixture was stirred at 25° C. for 2 hours. The mixture was diluted with water (20 mL) and extracted with DCM (30 mL×2), the organic layers were combined, dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford the title compound (11.00 mg, 26.60 μmol, 59.46% yield, 95% purity) was obtained as white solid. LCMS: 393/395 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.59 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.24 (m, 1H), 7.02-7.09 (m, 1H), 6.75 (s, 1H), 4.69 (s, 2H), 4.55 (t, J=7.76 Hz, 1H), 4.40 (t, J=6.42 Hz, 2H), 3.86 (t, <J=5.81 Hz, 2H), 3.47 (q, J=6.72 Hz, 2H), 3.23 (s, 3H), 2.85 (t, J=5.75 Hz, 2H).

Compound 217: N-(3-Chloro-4-fluorophenyl)-2,3-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. O₅-tert-butyl O₃-ethyl 2-allyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

To a solution of 05-tert-butyl 03-ethyl 2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate (20.00 g, 67.72 mmol, 1.00 eq) and 3-bromoprop-1-ene (12.29 g, 101.58 mmol, 1.50 eq) in DMF (200.00 mL) was added Cs₂CO₃ (55.16 g, 169.30 mmol, 2.50 eq). Then the mixture was stirred at 25° C. for 16 h. TLC (petroleum ether:EtOAc=3:1) showed that 05-tert-butyl 03-ethyl 2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3,5-dicarboxylate was consumed completely and two new spots formed. The mixture was diluted with 100 mL of water and extracted with EtOAc (100 mL*3). The combined organic phase was washed with brine (100 mL) and dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified via column chromatography (SiO₂, Petroleum ether/Ethyl acetate=50/l to 3/1) to give the title compound (13.50 g, 40.25 mmol, 59.44% yield) as white solid and its regioisomer (9.50 g, 28.32 mmol, 41.83% yield) as white solid.

Step 2. tert-Butyl ethyl 2-(2-oxoethyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

To a solution of O₅-tert-butyl O₃-ethyl 2-allyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (1.00 g, 2.98 mmol, 1.00 eq) in THF (1.00 mL) and H₂O (500.00 μL) was added OsO₄ (75.80 mg, 298.15 μmol, 15.47 μL, 0.10 eq), followed by NaIO₄ (1.91 g, 8.94 mmol, 495.63 μL, 3.00 eq) at 0° C. The mixture was stirred at 25° C. for 5 hr. The mixture was quenched by saturated Na₂S₂O₃ (50 mL) and extracted with EA (80 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was used in the next step directly. The title compound (700.00 mg, crude) was obtained as colorless oil.

Step 3, O₅-tert-butyl O₃-ethyl2-[2-[[tert-butoxycarbonyl)methyl)amino]-methyl-amino]ethyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate

To a solution of tert-butyl N-methyl-N-(methylamino)carbamate (432.14 mg, 2.70 mmol, 1.30 eq) and O₅-tert-butyl O₃-ethyl 2-(2-oxoethyl)-6,7-dihydro-4H-pyrazolo [4,3-c]pyridine-3,5-dicarboxylate (700.00 mg, 2.07 mmol, 1.00 eq) in EtOH (15.00 mL) was added HOAc (1.25 mg, 20.75 μmol, 1.19 μL, 0.01 eq). The mixture was stirred at 20° C. for 5 hr. NaBH₃CN (391.16 mg, 6.22 mmol, 3.00 eq) was added and the mixture was stirred at 20° C. for 16 hr. The mixture was diluted with H₂O (50 mL) and extracted with EA (60 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA=15%˜25%) and then prep-HPLC (FA) to give the title compound (100.00 mg, 186.88 μmol, 9.03% yield, 90% purity) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ=4.38-4.60 (m, 4H), 4.17-4.31 (m, 2H), 3.51-3.67 (m, 2H), 2.77 (s, 3H), 2.67 (s, 2H), 2.55 (s, 3H), 1.40 (d, J=10.9 Hz, 18H), 1.31 (t, J=7.2 Hz, 3H).

Step 4. Ethyl2-[2-[methyl(methylamino)amino]ethyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate

O₅-tert-butyl O₃-ethyl 2-[2-[[tert-butoxycarbonyl(methyl)amino]-methyl-amino]ethyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3,5-dicarboxylate (50.00 mg, 103.82 μmol, 1.00 eq) was dissolved in HCl/dioxane (103.82 μmol, 2.00 mL, 4M, 1.00 eq) and the mixture was stirred at 25° C. for 1 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (40.00 mg, crude, 2HCl) as colorless oil.

Step 5. tert-Butyl2,3-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepine-10-carboxylate

To a solution of ethyl 2-[2-[methyl(methylamino)amino]ethyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylate (60.00 mg, 169.36 μmol, 1.00 eq, 2HCl) in MeOH (500.00 μL) was added CH₃ONa (45.74 mg, 846.80 μmol, 5.00 eq). The mixture was stirred at 25° C. for 2 hr. The mixture was stirred at 25° C. for another 16 hr. Additional CH₃ONa (20 mg) was added and the mixture was stirred at 25° C. for another 16 hr. The mixture was concentrated in vacuo to give a residue. The residue was dissolved in H₂O (500.00 μL) and THF (3.00 mL). To the solution were added Boc₂O (44.35 mg, 203.23 μmol, 46.68 μL, 1.20 eq) and NaHCO₃ (28.46 mg, 338.72 μmol, 13.18 μL, 2.00 eq). The mixture was stirred at 25° C. for 3 hr. The mixture was diluted with H₂O (10 mL) and extracted with EA (20 mL×2). The combined organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo to give the title compound (60.00 mg, crude) as brown oil.

Step 6, 2,3-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepin-1-one

To a solution of tert-butyl 2,3-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-c][1,2,5]triazepine-10-carboxylate (70.00 mg, 208.71 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (1.54 g, 13.51 mmol, 1.00 mL, 64.71 eq), the mixture was stirred at 25° C. for 16 hr. The mixture was concentrated in vacuo to give the title compound (77.00 mg, crude, TFA) as brown oil.

Step 7. N-(3-chloro-4-fluorophenyl)-2,3-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-Pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 2,3-dimethyl-4,5,8,9,10,11-hexahydropyrido[2,3]pyrazolo[2,4-c][1,2,5]triazepin-1-one (75.00 mg, 214.71 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (57.04 mg, 214.71 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (108.63 mg, 1.07 mmol, 148.81 μL, 5.00 eq). The mixture was stirred at 25° C. for 16 hr. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford the title compound (20.00 mg, 48.82 μmol, 22.74% yield, 99.3% purity) as white solid. LCMS: 407 [M+1]. ¹H NMR (400 MHz, CDCl₃) δ=7.61 (dd, J=2.6, 6.5 Hz, 1H), 7.19-7.25 (m, 1H), 7.02-7.09 (t, 1H), 6.70 (s, 1H), 4.73 (s, 2H), 4.53 (t, J=6.1 Hz, 2H), 3.88 (t, J=5.8 Hz, 2H), 3.61 (t, J=6.1 Hz, 2H), 3.25 (s, 3H), 2.86 (t, J=5.8 Hz, 2H), 2.69 (s, 3H).

Compound 218: (R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-methyl-carbamate

To a solution of tert-butyl N-amino-N-methyl-carbamate (2.00 g, 13.68 mmol, 1.00 eq) in DMF (20.00 mL) were added 2-bromoethoxy-tert-butyl-dimethyl-silane (3.60 g, 15.05 mmol, 1.10 eq) and DIE A (2.30 g, 17.78 mmol, 3.11 mL, 1.30 eq). The mixture was stirred at 90° C. for 32 hr. The mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL×2). The combined organic layer was washed with H₂O (50 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE/EA: 0%˜10%) to get tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-methyl-carbamate (4.00 g, 10.51 mmol, 76.82% yield, 80% purity) as colorless oil.

Step 2. tert-butylN-[allyl-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]-N-methyl-carbamate

To a solution of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-methyl-carbamate (4.00 g, 10.51 mmol, 1.00 eq) and 3-bromoprop-1-ene (1.91 g, 15.76 mmol, 1.50 eq) in DMF (40.00 mL) was added DIEA (1.77 g, 13.66 mmol, 2.39 mL, 1.30 eq). Then the mixture was heated to 65° C. for 16 hr. The mixture was diluted with H₂O (100 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layer was washed with H₂O (50 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA: 0%˜5%) to give tert-butylN-[allyl-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]-N-methyl-carbamate (2.80 g, 6.50 mmol, 61.85% yield, 80% purity) as colorless oil.

Step 3, 2-[allyl(methylamino)amino]ethanol

To a solution of tert-butyl N-[allyl-[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]-N-methyl-carbamate (2.00 g, 4.64 mmol, 1.00 eq) in EtOAc (20.00 mL) was added HCl/EtOAc (4 M, 10.00 mL, 8.62 eq). The mixture was stirred at 10° C. for 3 hr. The mixture was concentrated in vacuo to get 2-[allyl(methylamino)amino]ethanol (1.30 g, crude, HCl) as brown oil.

Step 4. tert-butyl(6R)-3-[[allyl(2-hydroxyethyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of (6R)-5-tert-butoxycarbonyl-6-methyl-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3-carboxylic acid (1.00 g, 3.35 mmol, 1.00 eq) and 2-[allyl(methylamino)amino]ethanol (888.61 mg, 5.33 mmol, 1.50 eq, HCl) in DMF (20.00 mL) were added PYBOP (2.03 g, 3.91 mmol, 1.10 eq), HOBt (528.36 mg, 3.91 mmol, 1.10 eq) and DIEA (2.30 g, 17.77 mmol, 3.10 mL, 5.00 eq). The mixture was stirred at 40° C. for 16 hr. The mixture was diluted with H₂O (100 mL) and extracted with ethyl acetate (200 mL×2). The combined organic layer was washed with H₂O (100 mL×2), 1N HCl (50 mL), saturated NaHCO₃ (50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Petroleum ether:Ethyl acetate: 60%˜100%) to get tert-butyl(6R)-3-[[allyl(2-hydroxyethyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (860.00 mg, 1.92 mmol, 58.08% yield, 88% purity) as white solid. LCMS: 394 [M+1].

Step 5, tert-butyl(6R)-3-[[allyl(2-methylsulfonyloxyethyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl (6R)-3-[[allyl(2-hydroxyethyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (800.00 mg, 1.79 mmol, 1.00 eq) and DIEA (462.46 mg, 3.58 mmol, 624.95 μL, 2.00 eq) in DCM (8.00 mL) was added a solution of MsCl (246.05 mg, 2.15 mmol, 166.25 μL, 1.20 eq) in DCM (500.00 μL) dropwise at 0° C. The mixture was stirred at 0° C. for 0.5 hr. MsCl (205.05 mg, 1.79 mmol, 138.55 μL, 1.00 eq) was added and the mixture was stirred at 10° C. for 0.5 hr. The mixture was diluted with H₂O (50 mL) and extracted with DCM (100 mL). The organic layer was washed with 0.5 N HCl (20 mL), saturated NaHCO₃ (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo to give the title compound (800.00 mg, crude) as colorless oil. LCMS: 472 [M+1].

Step 6, tert-Butyl (R)-3-allyl-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl (6R)-3-[[allyl (2-methylsulfonyloxyethyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (800.00 mg, 1.70 mmol, 1.00 eq) in THF (10.00 mL) was added NaH (203.58 mg, 5.09 mmol, 60% purity, 3.00 eq) at 0° C. The mixture was stirred at 25° C. for 16 hr. Additional NaH (203.58 mg) added and the mixture was heated to 40° C. for 16 h. The mixture was quenched by 0.5 N HCl (20 mL) and extracted with ethyl acetate (80 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE:EA:30%˜50%) to afford the title compound (450.00 mg, 970.81 μmol, 57.11% yield, 81% purity) as white solid. LCMS: 376 [M+1].

Step 7, (R)-3-Allyl-2,9-dimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl (R)-3-allyl-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (250.00 mg, 539.34 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (3.12 g, 27.35 mmol, 2.02 mL, 50.71 eq). The mixture was stirred at 10° C. for 2 hr. The mixture was concentrated in vacuo to get the title compound (212.00 mg, crude, TFA) as brown oil.

Step 8. (R)-3-Allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-3-allyl-2,9-dimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (212.00 mg, 544.47 μmol, 1.00 eq, TFA) in DCM (5.00 mL) were added phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (139.51 mg, 544.47 μmol, 1.00 eq) and TEA (330.57 mg, 3.27 mmol, 452.83 μL, 6.00 eq). The mixture was stirred at 30° C. for 16 hr. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford the title compound (150.00 mg, 335.68 μmol, 61.65% yield, 97.9% purity) as white solid. 58.48 mg desired product was produced. LCMS: 438 [M+1]; ¹H NMR (400 MHz, CD₃OD) δ 7.82-7.84 (m, 1H), 7.70-7.72 (m, 1H), 7.29 (t, J=9.05 Hz, 1H), 5.83 (m, 1H), 5.14-5.23 (m, 2H), 4.96-5.09 (m, 2H), 4.31-4.50 (m, 3H), 3.61 (t, J=6.36 Hz, 2H), 3.45-3.47 (m, 2H), 3.21 (s, 3H), 3.04 (dd, 1H), 2.66-2.70 (d, 1H), 1.22 (d, J=6.85 Hz, 3H).

Compound 219: (R)—N—O-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-propyl-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide (Compound 218, 25 mg, 57.15 μmol, 1 eq) in MeOH (10 mL) was added Pd/C (2 mg, 10% purity, 1.00 eq) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (20 psi) at 15° C. for 20 min. The mixture was combined with (1753, 5 mg) to diluted with MeOH (20 mL), filtered and concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford 13 mg of the title compound as a white solid. LCMS: 440 [M+1]; ¹H NMR (400 MHz, CD₃OD) δ=7.81-7.83 (m, 1H), 7.70-7.72 (m, 1H), 7.28 (t, J=8.97 Hz, 1H), 4.92-5.08 (m, 2H), 4.33-4.49 (m, 3H), 3.56 (t, J=6.40 Hz, 2H), 3.21 (s, 3H), 3.03-3.05 (dd, 1H), 2.79-2.81 (m, 2H), 2.67 (d, J=15.81 Hz, 1H), 1.42-1.48 (m, 2H), 1.21 (d, J=6.90 Hz, 3H), 0.86 (t, J=7.40 Hz, 3H).

Compound 220: (R)—N-(3-Cyano-4-fluorophenyl)-3-(2-hydroxyethyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. (R)—N-(3-Cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-(2-oxoethyl)-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide (Compound 218, 70 mg, 156.65 μmol, 1.00 eq) in THF (4.00 mL) and H₂O (2.00 mL) were added OsO₄ (7.97 mg, 31.33 μmol, 1.63 μL, 0.20 eq) and NaIO₄ (100.52 mg, 469.95 μmol, 26.04 μL, 3.00 eq). The mixture was stirred at 15° C. for 6 hr. The mixture was diluted with H₂O (10 mL) and extracted with EA (20 mL×2). The combined organic layers were washed sat. Na₂S₂O₃ (10 mL×2), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (Petroleum ether/Ethyl acetate=1:1˜0:1) to afford the title compound (40 mg, 91.02 μmol, 58.11% yield) as brown oil.

Step 2. (R)—N-(3-Cyano-4-fluorophenyl)-3-(2-hydroxyethyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-(2-oxoethyl)-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5, l-d][1,2,5]tri azepine-10-carboxamide (20.00 mg, 45.51 μmol, 1.00 eq) in THF (1.00 mL) and EtOH (100.00 μL) was added NaBH₄ (5.16 mg, 136.53 μmol, 3.00 eq) at 0° C. The mixture was stirred at 15° C. for 30 min. The mixture was quenched with sat. NH₄Cl (10 mL) and extracted with EA (10 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (FA). The title compound (3.77 mg, 8.10 μmol, 17.79% yield, 94.8% purity) was obtained as white solid. LCMS: 442 [M+1]; ¹H NMR (400 MHz, CD₃OD) δ=7.83 (dd, J=2.75, 5.56 Hz, 1H), 7.71 (m, 1H), 7.28 (t, J=9.05 Hz, 1H), 4.98-5.08 (m, 1H), 4.97 (s, 1H), 4.31-4.54 (m, 3H), 3.68 (t, J=6.30 Hz, 2H), 3.59 (t, J=5.56 Hz, 2H), 3.27 (s, 3H), 3.02 (dd, J=5.75, 15.65 Hz, 1H), 2.93 (d, J=3.42 Hz, 2H), 2.67 (d, J=16.14 Hz, 1H), 1.22 (d, J=6.85 Hz, 3H).

Compound 221: (R)—N-(3-Cyano-4-fluorophenyl)-3-(2,2-difluoroethyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)—N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo-3-(2-oxoethyl)-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide (20.00 mg, 45.51 μmol, 1.00 eq) in DCM (2.00 mL) was added DAST (44.01 mg, 273.06 μmol, 36.08 μL, 6.00 eq) at −40° C. The mixture was stirred at 0° C. for 30 min. The mixture was diluted with H₂O (10 mL) and extracted with DCM (10 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (FA) to give the title compound (3.67 mg, 7.65 μmol, 16.81% yield, 96.2% purity) as white solid. LCMS: 462 [M+1]; ¹H NMR (400 MHz, CD₃OD) δ=7.83 (dd, J=2.7, 5.5 Hz, 1H), 7.71 (m, 1H), 7.28 (t, J=9.0 Hz, 1H), 5.72-6.05 (m, 1H), 4.92-5.07 (m, 2H), 4.33-4.56 (m, 3H), 3.70 (s, 2H), 3.25 (s, 3H), 3.12-3.22 (m, 2H), 3.04 (dd, J=5.7, 15.8 Hz, 1H), 2.69 (d, J=15.8 Hz, 1H), 1.22 (d, J=6.8 Hz, 3H).

Compound 222: (R)—N-(3-Cyano-4-fluorophenyl)-3-(3-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl (R)-3-(3-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate and tert-butyl (9R)-3-(2-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl (R)-3-allyl-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (30.00 mg, 64.72 μmol, 1.00 eq) and Rh(PPh₃)₃Cl (11.98 mg, 12.94 μmol, 0.20 eq) in THF (1.00 mL) was added 1,3,2-benzodioxaborole (1 M, 40.42 μL, 5.00 eq). The mixture was stirred at 0° C. for 1 hr. Then a solution of NaOH (18.12 mg, 453.04 μmol, 7.00 eq) in H₂O (500.00 μL) was added at −30° C., H₂O₂ (205.07 mg, 1.81 mmol, 173.79 μL, 30% purity, 27.95 eq) was added and the mixture was stirred at 10° C. for 1 hr. The mixture was diluted with H₂O (20 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed with aqueous NaOH (0.25 N, 30 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford tert-butyl (R)-3-(3-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (10 mg, 25.41 μmol, 39.27% yield) as colorless oil and tert-butyl (9R)-3-(2-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (2 mg, 5.08 μmol, 7.85% yield) as colorless oil.

Step 2. (R)-3-(3-Hydroxypropyl)-2,9-dimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a mixture of tert-butyl (R)-3-(3-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-1 OH-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (98 mg, 249.06 μmol, 1 eq) in DCM (3 mL) was added TFA (4.62 g, 40.52 mmol, 3 mL, 162.68 eq). The mixture was stirred at 20° C. for 0.5 hr. The mixture was concentrated under reduced pressure to give a residue. The title compound (103 mg, crude, TFA) was obtained as yellow oil.

Step 3. (R)—N-(3-Cyano-4-fluorophenyl)-3-(3-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]tri azepine-10-carboxamide

To a solution of (R)-3-(3-hydroxypropyl)-2,9-dimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (103 mg, 252.83 μmol, 1 eq, TFA) and phenyl 3-cyano-4-fluoro-benzoate (60.99 mg, 252.83 μmol, 1 eq) in DCM (5 mL) was added TEA (153.50 mg, 1.52 mmol, 211.15 μL, 6 eq). The mixture was stirred at 20° C. for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA) to give the title compound (60.2 mg, 130.85 μmol, 51.75% yield, 99.0% purity) as white solid. LCMS: 456 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dd, J=2.64, 5.40 Hz, 1H), 7.56-7.62 (m, 1H), 7.13 (t, J=8.66 Hz, 1H), 6.74 (s, 1H), 5.15 (t, J=6.71 Hz, 1H), 4.83 (d, J=16.31 Hz, 1H), 4.47-4.48 (m, 1H), 4.45-4.53 (m, 3H), 3.69-3.72 (m, 2H), 3.59-3.62 (m, 2H), 3.25 (s, 3H), 2.91-3.08 (m, 3H), 2.67 (d, J=16.06 Hz, 1H), 1.71-1.77 (m, 2H), 1.19 (d, J=6.90 Hz, 3H).

Compound 223: (9R)—N-(3-Cyano-4-fluorophenyl)-3-(2-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. (9R)-3-(2-Hydroxypropyl)-2,9-dimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a mixture of tert-butyl (9R)-3-(2-hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-1 OH-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (52.26 mg, 132.82 μmol, 1 eq) in DCM (3 mL) was added TFA (4.62 g, 40.52 mmol, 3.00 mL, 305.07 eq). The mixture was stirred at 20° C. for 0.5 hr. The mixture was concentrated under reduced pressure to afford the title compound (40.5 mg, crude, TFA) as yellow oil.

Step 2. (9R)—N-(3-Cyano-4-fluorophenyl)-3-(2-hydroxyprolyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (9R)-3-(2-hydroxypropyl)-2,9-dimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (40.5 mg, 99.41 μmol, 1 eq, TFA) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (25.47 mg, 99.41 μmol, 1 eq) in DCM (3 mL) was added TEA (60.36 mg, 596.46 μmol, 83.02 μL, 6 eq). The mixture was stirred at 20° C. for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA). The title compound (30.22 mg, 64.95 μmol, 65.34% yield, 97.9% purity) was obtained as white solid. LCMS: 456 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J=2.76, 5.40 Hz, 1H), 7.52-7.66 (m, 1H), 7.14 (t, J=8.66 Hz, 1H), 6.67 (s, 1H), 5.06-5.25 (m, 1H), 4.84 (m, J=10.29 Hz, 1H), 4.39-4.63 (m, 3H), 3.56-3.91 (m, 3H), 3.28 (d, J=4.27 Hz, 3H), 2.84-3.10 (m, 2H), 2.58-2.74 (m, 2H), 1.08-1.22 (m, 6H).

Compound 224: (R)—N-(3-Cyano-4-fluorophenyl)-2,3,9-trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-methyl-carbamate

To a solution of tert-butyl N-amino-N-methyl-carbamate (10 g, 68.41 mmol, 1 eq) and 2-bromoethoxy-tert-butyl-dimethyl-silane (18.00 g, 75.25 mmol, 1.1 eq) in DMF (85 mL) was added DIEA (11.49 g, 88.93 mmol, 15.49 mL, 1.3 eq). The mixture was stirred at 90° C. for 48 hr. The mixture was diluted with 50 mL of water and extracted with EtOAc (50 mL×3), and then the combined organic layers were washed with 0.5N HCl (50 mL×1), water (50 mL×2) and brine (50 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 30/1 (9.7 g, 27.40 mmol, 40.05% yield, 86% purity) to afford the title compound as colorless liquid.

Step 2. tert-Butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethyl-methyl-amino]-N-methyl-carbamate

To a solution of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethylamino]-N-methyl-carbamate (5 g, 14.12 mmol, 1 eq) in DMF (5 mL) was added Mel (12.03 g, 84.73 mmol, 5.27 mL, 6 eq) at 15° C., and then the mixture was heated to 70° C. with stirring for 3 h. The mixture was quenched with 0.5 N HCl (30 mL) and extracted with EtOAc (30 mL×4), and the organic layers were washed with water (30 mL×2) and brine (30 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=100/l to 30/1). The title compound (2.7 g, 8.48 mmol, 60.03% yield) was obtained as yellow liquid.

Step 3, 2-[Methyl(methylamino)amino]ethanol

To a solution of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxyethyl-methyl-amino]-N-methyl-carbamate (2.94 g, 9.23 mmol, 1 eq) in dioxane (6 mL) was added HCl/dioxane (4 M, 6.92 mL, 3 eq), and then the mixture was stirred at 15° C. for 3 h. The mixture was concentrated in vacuo. The residue was not purified. The title compound (1.35 g, crude, HCl) was obtained as colorless oil.

Step 4. tert-Butyl (6R)-3-[[2-hydroxyethyl(methyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of (6R)-5-tert-butoxycarbonyl-6-methyl-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-3-carboxylic acid (1.0 g, 3.55 mmol, 1 eq) in pyridine (10 mL) was added EDCI (817.76 mg, 4.27 mmol, 1.2 eq), and the mixture was heated to 15° C. with stirring for 16 h. The mixture was diluted with 20 mL of water and extracted with EtOAc (20 mL×3), and the combined organic layers were washed with aqueous solution of HCl (1N, 30 mL×3), saturated aqueous solution of NaHCO₃ (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=10/l to 1/3). The title compound (970 mg, 2.64 mmol, 74.26% yield) was obtained as red solid.

Step 5. tert-Butyl (6R)-6-methyl-3-[methyl-[methyl(2-methylsulfonyl oxyethyl)amino]carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl (6R)-3-[[2-hydroxyethyl(methyl)amino]-methyl-carbamoyl]-6-methyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (970 mg, 2.64 mmol, 1 eq) and DIEA (1.36 g, 10.56 mmol, 1.84 mL, 4 eq) in DCM (25 mL) was added MsCl (362.88 mg, 3.17 mmol, 245.19 μL, 1.2 eq) at 0° C. with stirring for 1 h. The mixture was diluted with 20 mL of water and extracted with DCM (20 mL×3), and the combined organic layers were washed with aqueous solution of HCl (1N, 30 mL×3), saturated aqueous solution of NaHCO₃ (20 mL) and brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was not purified. The title compound (1.2 g, crude) was obtained as yellow solid and used directly in the next step.

Step 6. tert-Butyl (R)-2,3,9-trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl (6R)-6-methyl-3-[methyl-[methyl(2-methylsulfonyl oxyethyl)amino]carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (1.2 g, crude, 2.69 mmol, 1 eq) in THF (25 mL) was added NaH (269.31 mg, 6.73 mmol, 60% purity, 2.5 eq) at 0° C., and then the mixture was heated to 40° C. with stirring for 16 h. The mixture was quenched with aqueous solution of HCl (1 N, 10 mL) and extracted with EtOAc (20 mL×3), and the combined organic layers were washed with saturated aqueous solution of NaHCO₃ (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was not purified and used in the next step. 850 mg of the title compound was obtained as yellow oil.

Step 7. (R)-2,3,9-Trimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl (R)-2,3,9-trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (200 mg, 89% purity, 509.41 μmol, 1 eq) in DCM (3 mL) was added TFA (462.00 mg, 4.05 mmol, 0.3 mL, 7.95 eq), and the mixture was stirred at 15° C. for 1 h. The mixture was concentrated in vacuo.

The residue was not purified and used directly in the next step. The title compound (190 mg, crude, TFA) was obtained as yellow oil.

Step 8. (R)—N-(3-Cyano-4-fluorophenyl)-2,3,9-trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-2,3,9-trimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (95 mg, 261.47 μmol, 1 eq, TFA) in DCM (3 mL) was added TEA (158.75 mg, 1.57 mmol, 218.36 μL, 6 eq) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (70.35 mg, 274.54 μmol, 1.05 eq), and the mixture was stirred at 15° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC(FA) to obtain the title compound (57 mg, 138.26 μmol, 52.88% yield, 99.8% purity) as white solid. LCMS: 412[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.81 (dd, J=2.76, 5.52 Hz, 1H), 7.60 (m, J=2.76, 4.58, 9.10 Hz, 1H), 7.15 (t, J=8.72 Hz, 1H), 6.71 (s, 1H), 5.14-5.23 (m, 1H), 4.88 (d, J=15.81 Hz, 1H), 4.50-4.60 (m, 3H), 3.64 (t, J=6.09 Hz, 2H), 3.27 (s, 3H), 3.05 (dd, J=5.96, 15.87 Hz, 1H), 2.66-2.73 (m, 4H), 1.19 (d, J=6.90 Hz, 3H).

Compound 225: (R)—N-(4-Fluoro-3-(trifluoromethyl)phenyl)-2,3,9-trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-2,3,9-trimethyl-2,3,4,5,8,9,10,11-octahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (95 mg, 261.47 μmol, 1 eq, TFA) in DCM (3 mL) was added TEA (158.75 mg, 1.57 mmol, 218.36 μL, 6 eq) and phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl]carbamate (82.15 mg, 274.54 μmol, 1.05 eq). The mixture was stirred at 15° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to obtain the title compound (57 mg, 125.43 μmol, 47.97% yield, 100% purity) as white solid. LCMS: 455[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.69 (dd, J=2.70, 6.09 Hz, 1H), 7.57-7.63 (m, 1H), 7.13 (t, J=9.41 Hz, 1H), 6.65 (s, 1H), 5.14-5.24 (m, 1H), 4.87 (d, J=15.69 Hz, 1H), 4.49-4.59 (m, 3H), 3.60-3.65 (m, 2H), 3.25 (s, 3H), 3.04 (dd, J=5.90, 15.81 Hz, 1H), 2.65-2.71 (m, 4H), 1.17 (d, J=6.90 Hz, 3H).

Compound 226: N-(3-Chloro-4-fluorophenyl)-4-hydroxy-2-methyl-1-oxo-4-(trifluoromethyl)-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl 3-[benzyloxycarbonylamino(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid (6.00 g, 22.45 mmol, 1.00 eq) and benzyl N-(methylamino)carbamate (6.32 g, 29.19 mmol, 1.30 eq, HCl) in DMF (50.00 mL) were added PYBOP (1.29 g, 2.47 mmol, 0.11 eq), HOBt (3.34 g, 24.69 mmol, 1.10 eq) and DIPEA (17.41 g, 134.69 mmol, 23.52 mL, 6.00 eq) at 25° C. The mixture was stirred at 25° C. for 3 h. LCMS indicated that most of 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid remained and a little desired product was detected. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue which was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 1/1) to recover 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid.

The recovered 5-tert-butoxycarbonyl-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxylic acid was dissolved in the 50 mL of DMF. To the solution were added PYBOP (12.85 g, 24.69 mmol, 1.10 eq), HOBt (3.34 g, 24.69 mmol, 1.10 eq), DIPEA (17.41 g, 134.69 mmol, 23.52 mL, 6.00 eq) and benzyl N-(methylamino)carbamate (6.32 g, 29.19 mmol, 1.30 eq, HCl). The mixture was stirred at 25° C. for 16 h. The mixture was diluted with 50 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with saturated NaHCO₃ (30 mL), HCl (1N, 30 mL) and brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to give the residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=l/0 to 1/1) to give the title compound (2.60 g, 5.31 mmol, 23.65% yield, 87.7% purity) as white solid.

Step 2. tert-Butyl 3-[amino(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl 3-[benzyloxycarbonylamino(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (2.60 g, 6.05 mmol, 1.00 eq) in MeOH (50.00 mL) was added Pd/C (500.00 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (15 psi) at 25° C. for 16 hours. The mixture was diluted with 30 mL of MeOH, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=30/l to 1/4) to give the title compound (1.30 g, 4.18 mmol, 69.12% yield, 95% purity) as white solid.

Step 3, tert-Butyl3-[[(Z)-[1-(bromomethyl)-2,2,2-trifluoro-ethylidene]amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of tert-butyl 3-[amino(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (150.00 mg, 507.89 μmol, 1.00 eq) and 3-bromo-1,1,1-trifluoro-propan-2-one (145.47 mg, 761.84 μmol, 79.06 μL, 1.50 eq) in DCM (15.00 mL) was added TsOH.H₂O (19.32 mg, 101.58 μmol, 0.20 eq) in one portion at 25° C. The mixture was stirred at 25° C. for 2 hours. 3-Bromo-1,1,1-trifluoro-propan-2-one (77.59 mg, 406.31 μmol, 42.17 μL, 0.80 eq) was added into the mixture and the mixture was stirred at 25° C. for another 12 hours. The reaction mixture was quenched by H₂O (5 mL), and then extracted with DCM (10×2 mL). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (PE/EA=1/1). The title compound (210.00 mg, 448.46 μmol, 88.30% yield) was obtained as white solid. LCMS: 411 [M-56].

Step 4. tert-Butyl 2-methyl-1-oxo-4-(trifluoromethyl)-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 3-[[(Z)-[1-(bromomethyl)-2,2,2-trifluoro-ethylidene]amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (100.00 mg, 213.55 μmol, 1.00 eq) in DMF (5.00 mL) was added Cs₂CO₃ (139.16 mg, 427.10 μmol, 2.00 eq) in one portion at 25° C. under N₂. The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with H₂O (40 mL) and then extracted with EtOAc (10×2 mL). The combined organic layers were washed with brine (15 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether:Ethyl acetate=3:1). The title compound (45.00 mg, 116.17 μmol, 54.40% yield) was obtained as yellow oil.

Step 5, 2-Methyl-4-(trifluoromethyl)-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl 2-methyl-1-oxo-4-(trifluoromethyl)-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (100.00 mg, 258.16 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (29.44 mg, 258.16 μmol, 19.12 μL, 1.00 eq) with stirring at 30° C. for 1 h. The mixture was concentrated under reduced pressure to give the title compound (40.00 mg, 99.69 μmol, 38.61% yield, TFA) as yellow oil, which was used directly for next step.

Step 6. N-(3-Chloro-4-fluorophenyl)-4-hydroxy-2-methyl-1-oxo-4-(trifluoromethyl)-1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 2-methyl-4-(trifluoromethyl)-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (35.00 mg, 87.23 μmol, 1.00 eq, TFA) and TEA (52.96 mg, 523.38 μmol, 72.55 μL, 6.00 eq) in DCM (8.00 mL) was added phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (23.17 mg, 87.23 μmol, 1.00 eq) with stirring at 30° C. for 1 h. The mixture was directly evaporated in vacuo and purified by prep-HPLC (FA) to afford the title compound as white solid (12 mg, 29.46%). LCMS: 459[M+1]; ¹H NMR (400 MHz, CDCl₃) δ 7.58 (dd, J=2.63, 6.54 Hz, 1H), 7.16-7.24 (m, 1H), 7.02-7.10 (m, 1H), 6.65 (s, 1H), 4.76 (s, 2H), 3.82-3.92 (t, 2H), 3.45 (s, 3H), 3.06 (d, J=1.71 Hz, 1H), 2.96 (m, J=6.19 Hz, 2H), 2.22 (s, 1H).

Compound 227: N-(3-Chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl 3-[[Z)-[1-(acetoxymethyl)-2-chloro-ethylidene]amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl 3-[amino(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (200.00 mg, 677.19 μmol, 1.00 eq) and p-TsOH (11.66 mg, 67.72 μmol, 0.10 eq) in DCM (15.00 mL) was added (3-chloro-2-oxo-propyl) acetate (132.54 mg, 880.35 μmol, 1.30 eq) with stirring at 25° C. under N₂ for 4 h. The mixture was diluted with 30 mL of DCM and washed with brine (50 mL×1). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=1:1) to give the title compound (250.00 mg, 584.28 μmol, 86.28% yield) as white solid.

Step 2. tert-Butyl 4-(acetoxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 3-[[(Z)-[1-(acetoxymethyl)-2-chloro-ethylidene]amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (250.00 mg, 584.28 μmol, 1.00 eq) in DMF (10.00 mL) were added Cs₂CO₃ (380.74 mg, 1.17 mmol, 2.00 eq) and TBAI (21.58 mg, 58.43 μmol, 0.10 eq) with stirring at 25° C. for 2 h. The mixture was diluted with 20 mL of water and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL×1), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The title compound (270.00 mg, crude) was obtained as yellow oil.

Step 3. tert-Butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 4-(acetoxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (250.00 mg, 638.70 μmol, 1.00 eq) in THF (10.00 mL) and H₂O (1.00 mL) was added LiOH.H₂O (53.60 mg, 1.28 mmol, 2.00 eq) with stirring at 25° C. for 2 h. The mixture was diluted with 20 mL of water and extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=1:3) to the title compound (160.00 mg, crude) as off-white gum.

Step 4, 4-(Hydroxymethyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (40.00 mg, 114.49 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (308.07 mg, 2.70 mmol, 200.05 μL, 23.60 eq) with stirring at 30° C. for 0.5 h. The mixture was concentrated in vacuo at 30° C. The title compound (45.00 mg, crude, TFA) was obtained as yellow oil.

Step 5. N-(3-Chloro-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 4-(hydroxymethyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′: 3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (45.00 mg, 123.87 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (34.55 mg, 130.06 μmol, 1.05 eq) in DCM (5.00 mL) was added TEA (75.21 mg, 743.21 μmol, 103.02 μL, 6.00 eq) with stirring at 25° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to give the title compound (18.00 mg, 42.35 μmol, 34.19% yield, 99% purity) as white solid. LCMS: 421[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.56 (s, 1H), 4.87 (s, 2H), 4.72 (s, 2H), 4.51 (s, 2H), 3.85 (t, J=5.75 Hz, 2H), 3.50 (s, 3H), 2.83 (t, J=5.75 Hz, 2H).

Compound 228: N-(3-Cyano-4-fluorophenyl)-4-(hydroxymethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 4-(hydroxymethyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (85.00 mg, 233.97 μmol, 1.00 eq, TFA) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (62.95 mg, 245.67 μmol, 1.05 eq) in DCM (5.00 mL) was added TEA (142.05 mg, 1.40 mmol, 194.59 μL, 6.00 eq) with stirring at 25° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (TFA) to give the title compound (12.05 mg, 28.71 μmol, 12.27% yield, 98% purity) as white solid. LCMS: 412 [M+1; ¹H NMR (400 MHz, CDCl₃) δ=7.77 (dd, J=2.81, 5.50 Hz, 1H), 7.57-7.64 (m, 1H), 7.14 (t, J=8.68 Hz, 1H), 6.86 (s, 1H), 4.88 (s, 2H), 4.73 (s, 2H), 4.51 (s, 2H), 3.86 (t, J=5.75 Hz, 2H), 3.51 (s, 3H), 2.84 (t, J=5.75 Hz, 2H).

Compound 229: N-(3-Chloro-4-fluorophenyl)-4-(1-hydroxypropyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl 4-formyl-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 4-(hydroxymethyl)-2-methyl-1-oxo-5,8,9,11-tetrahydropyrido[2,3]pyrazolo[2,4-d][1,2,5]triazepine-10-carboxylate (600.00 mg, 1.72 mmol, 1.00 eq) in DCM (30.00 mL) was added DMP (1.46 g, 3.43 mmol, 1.06 mL, 2.00 eq) with stirring at 25° C. for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, PE/EtOAc=10/1 to 3/1) to afford the title compound (450.00 mg, 1.30 mmol, 75.32% yield) as light yellow solid.

Step 2. tert-Butyl 4-(1-hydroxypropyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 4-formyl-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (50.00 mg, 143.94 μmol, 1.00 eq) in THF (10.00 mL) was added EtMgBr (3 M, 57.58 μL, 1.20 eq) dropwise at −78° C. under N₂. Then the mixture was warmed to 25° C. with stirring for 1 h. Then EtMgBr (3 M, 719.70 μL, 15.00 eq) was added in three portions at −78° C. and the mixture was warmed to 25° C. with stirring for one hour each time. The mixture was quenched with 10 mL of water and extracted with EtOAc (20 mL×3). The organic phase was collected and washed with brine (20 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=1:2) to give the title compound (14.00 mg, 37.09 μmol, 25.77% yield) as off-white oil.

Step 3, 4-(1-Hydroxypropyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl 4-(1-hydroxypropyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (14.00 mg, 37.09 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (77.00 mg, 675.32 μmol, 50.00 μL, 18.21 eq). Then the mixture was stirring at 25° C. for 1 h. The mixture was concentrated in vacuo to give the title compound (15.00 mg, crude, TFA) as yellow oil and used in the next step directly.

Step 4. N-(3-Chloro-4-fluorophenyl)-4-(1-hydroxypropyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 4-(1-hydroxypropyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′: 3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (15.00 mg, 38.33 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (10.18 mg, 38.33 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (31.03 mg, 306.64 μmol, 42.51 μL, 8.00 eq), then the mixture was stirring at 25° C. for 16 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to obtain the title compound (6.01 mg, 13.12 μmol, 34.23% yield, 98% purity) as white solid. LCMS: 449[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.57 (dd, J=2.63, 6.54 Hz, 1H), 7.17-7.23 (m, 1H), 7.02-7.09 (m, 1H), 5.11-5.15 (d, 1H), 4.93-5.01 (m, 1H), 4.71 (s, 2H), 4.60 (s, 2H), 4.44 (t, J=5.20, 7.03 Hz, 1H), 3.80-3.87 (m, 2H), 3.48 (s, 3H), 2.83 (t, J=5.75 Hz, 2H), 1.71-1.59 (m, 2H), 0.83 (t, J=7.40 Hz, 3H).

Compound 230: N-(3-Chloro-4-fluorophenyl)-4-(1-hydroxyethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl 4-(1-hydroxyethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 4-formyl-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (100.00 mg, 287.88 μmol, 1.00 eq) in THF (10.00 mL) was added dropwise MeMgBr (3 M, 576.67 μL, 6.00 eq) in three portions at −78° C. under N₂. Then the mixture was warmed to 25° C. with stirring for 4 h. The mixture was quenched with 10 mL of water and extracted with EtOAc (20 mL×3). The combined organic layers were collected and washed with brine (20 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=0:1) to give the title compound (24.00 mg, 66.04 μmol, 22.94% yield) as colorless oil.

Step 2, 4-(1-Hydroxyethyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl 4-(1-hydroxyethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (24.00 mg, 66.04 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (77.00 mg, 675.59 μmol, 50.00 μL, 10.23 eq), then the mixture was stirring at 25° C. for 1 h. The mixture was concentrated in vacuo. The title compound (25.00 mg, crude, TFA) was obtained as yellow oil and used in the next step directly.

Step 3. N-(3-Chloro-4-fluorophenyl)-4-(1-hydroxyethyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 4-(1-hydroxyethyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (25.00 mg, 66.26 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (17.60 mg, 66.26 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (53.64 mg, 530.05 μmol, 73.47 μL, 8.00 eq), then the mixture was stirring at 25° C. for 3 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA). The title compound (16.00 mg, 36.06 μmol, 54.42% yield, 98% purity) was obtained as white solid.

LCMS: 435 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.58 (dd, J=2.76, 6.53 Hz, 1H), 7.27-7.19 (m, J=2.70, 4.05, 8.94 Hz, 1H), 7.02-7.09 (m, 1H), 6.53 (s, 1H), 4.86-5.02 (m, 2H), 4.71 (s, 2H), 4.64 (m, J=6.65 Hz, 1H), 3.85 (t, J=5.84 Hz, 2H), 3.49 (s, 3H), 2.84 (t, J=5.77 Hz, 2H), 1.42 (d, J=6.65 Hz, 3

Compound 231: N-(3-Chloro-4-fluorophenyl)-4-(cyclopropyl(hydroxy)methyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl 4-(cyclopropyl(hydroxy)methyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl 4-formyl-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (200.00 mg, 575.75 μmol, 1.00 eq) in THF (10.00 mL) was added drop wise bromo(cyclopropyl)magnesium (0.458 M, 5.03 mL, 4.00 eq) under N₂ at −78° C. The mixture was warmed to 20° C. with stirring for 1 h. Then bromo(cyclopropyl)magnesium (0.458 M, 5.03 mL, 4.00 eq) was added dropwise at 0° C. and the mixture was warmed to 20° C. with stirring for 1 h. Bromo(cyclopropyl)magnesium (0.458 M, 12.57 mL, 10.00 eq) was added dropwise at 0° C. and the mixture was warmed to 20° C. with stirring for 2 h. The mixture was combined with an earlier batch (200 mg) and diluted with 10 mL of DCM, washed with HCl (1N, 30 mL) and brine (20 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EtOAc=1:1) and prep-HPLC(FA) to give 13 mg of the title compound as white solid.

Step 2, 4-(Cyclopropyl(hydroxy)methyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl 4-(cyclopropyl(hydroxy)methyl)-2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (13.00 mg, 33.38 μmol, 1.00 eq) in DCM (1.00 mL) was added TFA (38.94 mg, 341.48 μmol, 25.28 μL, 10.23 eq), then the mixture was stirring at 25° C. for 1 h. The mixture was concentrated in vacuo. The residue was not purified. The title compound (14.00 mg, crude, TFA) was obtained as yellow oil and used in the next step directly.

Step 3. N-(3-Chloro-4-fluorophenyl)-4-(cyclopropyl(hydroxy)methyl)-2-methyl-1-σxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 4-(cyclopropyl(hydroxy)methyl)-2-methyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (14.00 mg, 34.71 μmol, 1.00 eq, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (9.22 mg, 34.71 μmol, 1.00 eq) in DCM (3.00 mL) was added TEA (28.10 mg, 211.61 μmol, 38.49 μL, 8.00 eq), then the mixture was stirring at 25° C. for 3 h. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to give the title compound (8.50 mg, 18.20 μmol, 52.44% yield, 98.7% purity) as white solid. LCMS: 461 [M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.58 (dd, J=2.64, 6.53 Hz, 1H), 7.16-7.22 (m, 1H), 7.03-7.09 (m, 1H), 6.55 (s, 1H), 5.07-5.13 (m, 1H), 4.92-4.99 (m, 1H), 4.72 (d, J=2.89 Hz, 2H), 3.81-3.88 (m, 3H), 3.49 (s, 3H), 2.79-2.88 (m, 3H), 0.98-1.09 (m, 1H), 0.57-0.67 (m, 2H), 0.45-0.54 (m, 2H).

Compound 232: N-(3-Chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl 3-[[(E)-(2-hydroxy-1-methyl-ethylidene)amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl 3-[amino(methyl)carbamoyl]-2,4,6,7-tetrahydropyrazolo [4,3-c]pyridine-5-carboxylate (300.00 mg, 1.02 mmol, 1.00 eq) and p-TsOH (17.56 mg, 102.00 μmol, 0.10 eq) in DCM (20.00 mL) was added 1-hydroxypropan-2-one (377.81 mg, 5.10 mmol, 349.82 μL, 5.00 eq) with stirring at 20° C. under N₂ for 2 h. The mixture was directly evaporated. The residue was purified by prep-TLC (PE:EA=0:1) to give the title compound (240.00 mg, 682.98 μmol, 66.96% yield) as off-white oil.

Step 2. tert-Butyl3-[methyl-[(E)-(1-methyl-2-methylsulfonyloxy-ethylidene)amino]carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl 3-[[(E)-(2-hydroxy-1-methyl-ethylidene)amino]-methyl-carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (100.00 mg, 284.58 μmol, 1.00 eq) in DCM (3.00 mL) was added pyridine (45.02 mg, 569.15 μmol, 45.94 μL, 2.00 eq) followed by MsCl (65.20 mg, 569.15 μmol, 44.05 μL, 2.00 eq). The mixture was stirred at 20° C. for 20 hr. The mixture was diluted with H₂O (30 mL) and extracted with EA (50 mL×2). The combined organic layer was washed saturated Cu₂SO₄ (30 mL), dried over Na₂SO₄, filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE:EA=1:1). The title compound (70.00 mg, 162.98 μmol, 57.27% yield) was obtained as colorless oil.

Step 3. tert-Butyl 2,4-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a suspension of NaH (9.31 mg, 232.84 μmol, 60% purity, 2.00 eq) in THF (5.00 mL) was added a solution of tert-butyl 3-[methyl-[(E)-(1-methyl-2-methylsulfonyloxy-ethylidene)amino]carbamoyl]-2,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (50.00 mg, 116.42 μmol, 1.00 eq) in THF (500.00 μL) at −10° C. The mixture was stirred at 20° C. for 2 hr. The mixture was quenched by H₂O (10 mL) and extracted with EA (20 mL×2). The combined organic layers were dried over Na₂SO₄, filtered. The filtrate was concentrated in vacuo. The residue was purified by prep-TLC (PE:EA=1:1) to give the title compound (20.00 mg, 49.19 μmol, 42.25% yield, 82% purity) as colorless oil.

Step 4, 2,4-Dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl 2,4-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (20.00 mg, 59.99 μmol, 1.00 eq) in DCM (3.00 mL) was added TFA (3.08 g, 27.01 mmol, 2.00 mL, 450.31 eq). The mixture was stirred at 20° C. for 0.5 hr. The residue was concentrated in vacuo to afford the title compound (22.00 mg, crude, TFA) as brown oil.

Step 5. N-(3-Chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of 2,4-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (22.00 mg, 63.35 μmol, 1.00 eq, TFA) in DCM (5.00 mL) was added TEA (32.05 mg, 316.75 μmol, 43.90 μL, 5.00 eq) followed by phenyl 3-chloro-4-fluoro-benzoate (15.88 mg, 63.35 μmol, 1.00 eq). The mixture was stirred at 20° C. for 16 hr. The mixture was concentrated in vacuo. The residue was purified by prep-HPLC (FA) to afford the title compound (16.00 mg, 35.25 μmol, 55.65% yield, 89.2% purity) as white solid. LCMS: 405 [M+1]; ¹H NMR (400 MHz, DMSO-d6) δ=8.98 (s, 1H), 7.79 (dd, J=2.57, 6.85 Hz, 1H), 7.48 (m, J=2.69, 4.28, 9.05 Hz, 1H), 7.29-7.37 (m, 1H), 4.99 (s, 2H), 4.69 (s, 2H), 3.79 (t, J=5.62 Hz, 2H), 3.36 (s, 3H), 2.77 (t, J=5.56 Hz, 2H), 2.24 (s, 3H).

Compound 233: (R)—N-(3-Cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl (R)-3-(2-((benzyloxy)carbonyl)-1-methylhydrazine-1-carbonyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of (R)-5-(tert-butoxycarbonyl)-6-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (4.80 g, 17.06 mmol, 1.00 eq) and benzyl N-(methylamino)carbamate (4.81 g, 22.18 mmol, 1.30 eq, HCl) in DMF (30.00 mL) were added PYBOP (9.77 g, 18.77 mmol, 1.10 eq), HOBT (2.54 g, 18.77 mmol, 1.10 eq) and DIPEA (13.23 g, 102.37 mmol, 17.88 mL, 6.00 eq). The mixture was stirred at 25° C. for 3 hr. The reaction mixture was diluted with H₂O (100 mL) and extracted with EA (100 mL×3). The combined organic layers were separated, washed with H₂O (100 mL×3), 1N HCl (80 mL) and NaHCO₃ (sat.aq. 80 mL). The combined organic layer was dried over Na₂SO₄, filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO₂, PE/EA=10:1 to 1:3) to give the title compound (6.80 g, 15.33 mmol, 89.87% yield) as white solid.

Step 2. tert-Butyl (R)-6-methyl-3-n-methylhydrazine-1-carbonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl (R)-3-(2-((benzyloxy)carbonyl)-1-methylhydrazine-1-carbonyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.00 g, 4.51 mmol, 1.00 eq) in MeOH (20.00 mL) was added Pd/C (400.00 mg, 10% purity) under N₂. The suspension was degassed under vacuum and purged with H₂ several times. The mixture was stirred under H₂ (15 psi) at 25° C. for 16 hours. The reaction solution was filtered directly. The filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO₂, PE/EA=1:2-0:1 EA/MeOH=50:1) to afford the title compound (1.20 g, 3.88 mmol, 86.01% yield) as white solid.

Step 3. tert-Butyl (R,Z)-3-(2-(1-acetoxy-3-chloropropan-2-ylidene)-1-methylhydrazine-1-carbonyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a solution of tert-butyl (R)-6-methyl-3-(1-methylhydrazine-1-carbonyl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.80 g, 5.82 mmol, 1.00 eq) and (3-chloro-2-oxo-propyl) acetate (1.14 g, 7.56 mmol, 1.30 eq) in DCM (15.00 mL) was added p-TsOH (100.19 mg, 581.85 μmol, 0.10 eq). The mixture was stirred at 25° C. for 4 hr under N₂. The mixture was concentrated in vacuo. The residue was purified by column chromatography (PE:EA:30%˜50%) to afford the title compound (2.32 g, 5.25 mmol, 90.21% yield) as white solid.

Step 4. tert-Butyl (R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl (R,Z)-3-(2-(1-acetoxy-3-chloropropan-2-ylidene)-1-methylhydrazine-1-carbonyl)-6-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (2.00 g, 4.53 mmol, 1.00 eq) in THF (30.00 mL) was added DBU (1.38 g, 9.06 mmol, 1.37 mL, 2.00 eq). The mixture was heated to 70° C. for 16 hr. The mixture was cooled to 25° C. and added H₂O (10.00 mL). The reaction mixture was stirred at 25° C. for 5 hr. The mixture was diluted with H₂O (100 mL) and extracted with EA (50 mL×2). The combined organic layer was dried over Na₂SO₄, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (PE:EA:50%˜100%) to give 1 g of the title compound as yellow solid.

Step 5. (R)-4-(Hydroxymethyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl (R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (100.00 mg, 214.63 μmol, 1.00 eq) in DCM (5.00 mL) was added TFA (7.21 g, 63.21 mmol, 4.68 mL, 294.49 eq) at 0° C. slowly. The mixture was stirred at 25° C. for 1 hr. The mixture was concentrated in vacuo. The title compound was obtained as brown oil.

Step 6. (R)—N-(3-Cyano-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-4-(hydroxymethyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (95.00 mg, 251.78 μmol, 1.00 eq, TFA) and phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (64.51 mg, 251.78 μmol, 1.00 eq) in DCM (5.00 mL) was added TEA (127.39 mg, 1.26 mmol, 174.50 μL, 5.00 eq). The mixture was stirred at 25° C. for 3 hr. The mixture was diluted in H₂O (10 mL) and extracted with DCM (20 mL×2). The combined organic layers were washed 1N HCl (10 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-TLC (PE:EA=0:1) and prep-HPLC (base) to afford the title compound (25.00 mg, 57.18 μmol, 22.71% yield, 97.31% purity) as white solid. LCMS: 426[M+1]; ¹H NMR (400 MHz, Acetone) δ=8.55 (s, 1H), 8.06 (dd, J=2.7, 5.8 Hz, 1H), 7.91-7.81 (m, 1H), 7.31 (t, J=9.0 Hz, 1H), 5.19-4.95 (m, 4H), 4.70-4.58 (m, 1H), 4.40-4.33 (m, 2H), 3.40 (s, 3H), 2.95-3.25 (dd, J=6.1, 16.0 Hz, 1H), 2.88-2.85 (m, 1H), 2.61-2.65 (d, J=15.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 3H).

Compound 234: (R)—N-(3-Bromo-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-4-(hydroxymethyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (52.00 mg, 137.81 μmol, 1.00 eq, TFA) and phenyl N-(3-bromo-4-fluoro-phenyl)carbamate (42.74 mg, 137.81 μmol, 1.00 eq) in DCM (5.00 mL) was added TEA (69.72 mg, 689.05 μmol, 95.51 μL, 5.00 eq). The mixture was stirred at 25° C. for 3 hr. The mixture was concentrated in vacuo. The residue was purified by pre-HPLC (Base) twice to give the title compound (20.00 mg, 40.48 μmol, 29.37% yield, 97% purity) as white solid. LCMS: 479/481[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.74 (dd, J=2.6, 6.1 Hz, 1H), 7.31-7.29 (m, 1H), 7.06 (t, J=8.5 Hz, 1H), 6.57 (s, 1H), 5.20-5.11 (m, 1H), 4.90 (s, 2H), 4.86 (s, 1H), 4.87-4.84 (m, 1H), 4.57-4.46 (m, 3H), 3.53 (s, 3H), 3.33 (d, J=2.8 Hz, 1H), 3.03 (dd, J=5.5, 15.6 Hz, 1H), 2.80 (t, J=5.2 Hz, 1H), 2.67 (d, J=16.1 Hz, 1H), 1.18 (d, J=6.9 Hz, 3H).

Compound 235: (R)—N-(3-Chloro-4-fluorophenyl)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-4-(hydroxymethyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (52.00 mg, 137.81 μmol, 1.00 eg, TFA) and phenyl N-(3-chloro-4-fluoro-phenyl)carbamate (36.61 mg, 137.81 μmol, 1.00 eg) in DCM (5.00 mL) was added TEA (69.72 mg, 689.05 μmol, 95.51 μL, 5.00 eq). The mixture was stirred at 25° C. for 3 hr. The mixture was concentrated in vacuo. The residue was purified by pre-HPLC(FA), and then purified by prep-TLC (PE:EA=0:1). Further purification by prep-HPLC (Base) to afford the title compound (8.00 mg, 17.86 μmol, 12.96% yield, 97.1% purity) as white solid. LCMS: 435[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.61 (dd, J=2.6, 6.5 Hz, 1H), 7.18-7.25 (m, 1H), 7.04-7.11 (m, 1H), 6.55 (s, 1H), 5.16 (m, J=6.5 Hz, 1H), 4.90 (s, 2H), 4.86 (s, 1H), 4.45-4.56 (m, 3H), 3.53 (s, 3H), 3.33 (d, J=2.3 Hz, 1H), 2.98-3.07 (m, 1H), 2.80 (s, 1H), 2.67 (m, J=15.8 Hz, 1H), 1.18 (d, J=6.9 Hz, 3H).

Compound 236: (R)—N-(3-Bromo-4-fluorophenyl)-4-(2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

Step 1. tert-Butyl (R)-4-(2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate

To a solution of tert-butyl (R)-4-(hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (50.00 mg, 107.32 μmol, 1.00 eq) in DMF (1.00 mL) was added NaH (8.59 mg, 214.63 μmol, 60% purity, 2.00 eq) at −40° C. The mixture was stirred at −20° C. for 0.5 hr. Then a solution of 2,2-difluoroethyl trifluoromethanesulfonate (68.93 mg, 321.95 μmol, 3.00 eq) in DMF (300.00 μL) was added at −20° C. The reaction mixture was stirred at −20° C. for 0.5 hr. The reaction mixture was quenched by saturated NH₄Cl (10 mL) and extracted with EA (20 mL×2). The combined organic layer were washed with FLO (20 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. The title compound (40.00 mg, crude) was obtained as colorless oil.

Step 2. (R)-4-((2,2-Difluoroethoxy)methyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one

To a solution of tert-butyl (R)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxylate (40.00 mg, 93.58 μmol, 1.00 eq) in DCM (2.00 mL) was added TFA (27.01 mmol, 2.00 mL, 288.66 eq). The mixture was stirred at 25° C. for 1 hr. The mixture was concentrated in vacuo. The title compound (43.00 mg, crude, TFA) was obtained as brown oil.

Step 3. (R)—N-(3-Bromo-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a solution of (R)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (40.00 mg, 90.63 μmol, 1.00 eq, TFA) and phenyl N-(3-bromo-4-fluoro-phenyl)carbamate (28.11 mg, 90.63 μmol, 1.00 eq) in DCM (4.00 mL) was added TEA (45.85 mg, 453.15 μmol, 62.81 μL, 5.00 eq). The mixture was stirred at 25° C. for 5 hr. The mixture was diluted with H₂O (15 mL) and extracted with DCM (20 mL×2). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Base) to afford the title compound (18.00 mg, 32.63 μmol, 36.01% yield, 98.5% purity) as white solid. LCMS: 543/545[M+1]; ¹H NMR (400 MHz, CDCl₃) δ=7.75 (dd, J=2.7, 6.1 Hz, 1H), 7.24-7.28 (m, 1H), 7.02-7.11 (m, 1H), 6.54 (s, 1H), 5.77-6.10 (m, 1H), 5.12-5.21 (m, 1H), 4.93-5.04 (m, 2H), 4.87 (d, J=15.9 Hz, 1H), 4.49 (d, J=15.9 Hz, 1H), 4.41 (s, 2H), 3.66-3.77 (m, 2H), 3.51 (s, 3H), 3.35 (d, J=4.0 Hz, 1H), 3.03 (dd, J=6.0, 16.1 Hz, 1H), 2.68 (d, J=16.1 Hz, 1H), 1.17 (d, J=6.9 Hz, 3H).

Compound 237: (R)—N-(3-Cyano-4-fluorophenyl)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a mixture of (R)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (150.00 mg, 339.87 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added TEA (137.57 mg, 1.36 mmol, 188.45 μL, 4.00 eq), followed by phenyl N-(3-cyano-4-fluoro-phenyl)carbamate (87.08 mg, 339.87 μmol, 1.00 eq), the reaction mixture was stirred at 20° C. for 3 hours. The mixture was diluted in water (20 mL) and extracted with DCM (30 mL×3), the combined organic layers were dried with anhydrous Na₂SO₄, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(Base) to afford the title compound (48.00 mg, 96.11 μmol, 28.28% yield, 98% purity) as white solid. LCMS: 490[M+1]; ¹H NMR (400 MHz, CDCl₃) δ 7.79 (dd, J=2.82, 5.46 Hz, 1H), 7.58 (m, J=2.82, 4.55, 9.07 Hz, 1H), 7.14 (t, J=8.72 Hz, 1H), 6.52-6.72 (m, 1H), 5.75-6.09 (m, 1H), 5.15 (m, J=6.27 Hz, 1H), 4.91-5.03 (m, 2H), 4.87 (d, J=15.81 Hz, 1H), 4.50 (d, J=15.69 Hz, 1H), 4.33-4.44 (m, 2H), 3.66-3.77 (m, 2H), 3.50 (s, 3H), 3.34 (d, J=3.14 Hz, 1H), 2.98-3.06 (m, 1H), 2.68 (d, J=16.19 Hz, 1H), 1.14-1.19 (d, 3H).

Compound 238: (R)-4-((2,2-Difluoroethoxy)methyl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide

To a mixture of (R)-4-((2,2-difluoroethoxy)methyl)-2,9-dimethyl-2,5,8,9,10,11-hexahydro-1H-pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepin-1-one (150.00 mg, 339.87 μmol, 1.00 eq, TFA) in DCM (3.00 mL) was added TEA (137.57 mg, 1.36 mmol, 188.45 μL, 4.00 eq), followed by phenyl N-[4-fluoro-3-(trifluoromethyl)phenyl] carbamate (101.69 mg, 339.87 μmol, 1.00 eq), the reaction mixture was stirred at 20° C. for 3 hours. The mixture was diluted in water (20 mL) and extracted with DCM (30 mL×3), the combined organic layers were dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by prep-HPLC (Base) to afford the title compound (30.00 mg, 53.53 μmol, 15.75% yield, 95% purity) as white solid.

LCMS: 533[M+1]; ¹H NMR (400 MHz, CDCl₃) δ 7.68 (dd, J=2.82, 6.09 Hz, 1H), 7.56-7.62 (m, 1H), 7.14 (t, J=9.47 Hz, 1H), 6.57 (s, 1H), 5.76-6.08 (m, 1H), 5.16 (m, J=6.02 Hz, 1H), 4.92-5.02 (m, 2H), 4.88 (d, J=15.69 Hz, 1H), 4.46-4.55 (m, 1H), 4.39 (s, 2H), 3.65-3.76 (m, 2H), 3.50 (s, 3H), 3.34 (d, J=4.27 Hz, 1H), 2.97-3.07 (m, 1H), 2.67 (d, J=16.44 Hz, 1H), 1.14-1.21 (d, 3H).

Example 1: HBV Assembly Assay

The interference of compounds from this invention with HBV capsid assembly could be measured using an in vitro assembly assay based on fluorescence quenching, which was developed according to a method described by Zlotnick and coworkers (Nature Biotechnology 2006, 24:358). In a typical assay, a mutant HBV C150 protein (amino acids 1-150, C49A, C61A, C107A, 150C) is cloned into a T7 RNA-polymerase based expression vector, expressed in E. coli and purified to homogeneity as a dimer. The purified HBV core protein is desalted and labeled with BODIPY-FL Dye.

In a non-limiting embodiment, the assembly assay is conducted in 96-well plate format. The assembly reactions are carried out in 50 mM Hepes buffer, pH 7.5 and 150 mM NaCl. The compounds are pre-incubated with the HBV CA protein for 15 min, and the assembly reactions are initiated by addition of NaCl. The reaction is allowed to continue for 1 hour at room temperature. The changes in fluorescence between DMSO treated and compound treated samples are recorded and analyzed for assembly modulation.

Example 2: HBV Replication Inhibition Assay

HBV replication inhibition by the disclosed compounds were determined in cells infected or transfected with HBV or cells with stably integrated HBV, such as HepG2.2.15 cells (Sells et al. 1987). In this example, HepG2.2.15 cells were maintained in cell culture medium containing 10% fetal bovine serum (FBS), Geneticin, L-glutamine, penicillin and streptomycin. HepG2.2.15 cells were seeded in 96-well plates at a density of 40,000 cells/well and were treated with serially diluted compounds at a final DMSO concentration of 0.5% either alone or in combination by adding drugs in a checker box format. Cells were incubated with compounds for three days, after which medium was removed and fresh medium containing compounds was added to cells and incubated for another three days. At day 6, supernatant was removed and treated with DNase at 37° C. for 60 minutes, followed by enzyme inactivation at 75° C. for 15 minutes. Encapsidated HBV DNA was released from the virions and covalently linked HBV polymerase by incubating in lysis buffer (Affymetrix QS0010) containing 2.5 μg proteinase K at 50° C. for 40 minutes. HBV DNA was denatured by addition of 0.2 M NaOH and detected using a branched DNA (BDNA) QuantiGene assay kit according to manufacturer recommendation (Affymetrix). HBV DNA levels were also quantified using qPCR, based on amplification of encapsidated HBV DNA extraction with QuickExtraction Solution (Epicentre Biotechnologies) and amplification of HBV DNA using HBV specific PCR probes that can hybridize to HBV DNA and a fluorescently labeled probe for quantitation. In addition, cell viability of HepG2.2.15 cells incubated with test compounds alone or in combination was determined by using CellTitre-Glo reagent according to the manufacturer protocol (Promega). The mean background signal from wells containing only culture medium was subtracted from all other samples, and percent inhibition at each compound concentration was calculated by normalizing to signals from HepG2.2.15 cells treated with 0.5% DMSO using equation E1.

% inhibition=(DMSOave−Xi)/DMSOave×100%  E1:

where DMSOave is the mean signal calculated from the wells that were treated with DMSO control (0% inhibition control) and Xi is the signal measured from the individual wells. EC50 values, effective concentrations that achieved 50% inhibitory effect, were determined by non-linear fitting using Graphpad Prism software (San Diego, Calif.) and equation E2:

Y=Y min+(Y max−Y min)/(1+10(Log EC50−X)×HillSlope)  E2:

where Y represents percent inhibition values and X represents the logarithm of compound concentrations.

Selected disclosed compounds were assayed in the HBV replication assay (BDNA assay), as described above, and a representative group of these active compounds is shown in Table 7.

Table 7 shows EC₅₀ values obtained by the BDNA assay for a group of select compounds. In Table 7, “A” represents 1<EC₅₀<100; “B” represents 100<EC₅₀<500; “C” represents 500<EC₅₀<1000; and “D” represents EC₅₀>1000.

TABLE 7 Activity in BDNA-assay (EC₅₀) Com- DNA pound EC₅₀ ID Compound Name (nM) 001 N-(3-bromophenyl)-4-(hydroxymethyl)-2-methyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 002 4-(hydroxymethyl)-2-methyl-1-oxo-N-(m-tolyl)- A 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 003 N-(2-chloro-3-fluoropyridin-4-yl)-4- B (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 004 N-(3-bromo-2-fluorophenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 005 N-(3,4-difluorophenyl)-4-(hydroxymethyl)-2-methyl- A 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 006 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3,4,5- A trifluorophenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 007 N-(3-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 008 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3- A (trifluoromethyl)phenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 009 N-(3-ethylphenyl)-4-(hydroxymethyl)-2-methyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 010 N-(3-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 011_E1 (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 011_E2 (R*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 012 N-(3,4-dichlorophenyl)-4-(hydroxymethyl)-2-methyl- A 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 013 N-(5-chloro-2,4-difluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 014 N-(5-bromo-2,4-difluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 015 N-(3-bromo-4,5-difluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 016 N-(2,5-dimethylphenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 017 N-(5-bromo-2-methylphenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 018 N-(5-bromo-4-fluoro-2-methylphenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 019 4-(hydroxymethyl)-2-methyl-N-(3- C methylcyclohexyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 020 4-(hydroxymethyl)-N-(3-iodophenyl)-2-methyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 021 N-(3-(difluoromethyl)phenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 022 N-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 023 N-(2,3-dichloro-4-fluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 024 N-(3,4-dichloro-2-fluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 025 N-(4-chloro-3-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 026 N-(3-chloro-4-methylphenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 027 N-(4,5-dichloro-2-fluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 028_E1 (S*)-N-(3-chloro-4,5-difluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 029 4-(hydroxymethyl)-2-methyl-1-oxo-N-(3- A (pentafluoro-16-sulfanyl)phenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 030 N-(3-chlorophenyl)-4-(hydroxymethyl)-2-methyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 031_E1 (S*)-N-(3-chloro-4-fluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 031_E2 (R*)-N-(3-chloro-4-fluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 032_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 033_E1 (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 034_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 035_E1 (S*)-N-(4-fluoro-3-methylphenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide A 036 4-(fluoromethyl)-2-methyl-1-oxo-N-(3- (trifluoromethyl)phenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 037_E1 (S*)-N-(3-chlorophenyl)-4-(fluoromethyl)-2-methyl- A 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 038_E1 (S*)-N-(3-chloro-4-fluorophenyl)-4-(fluoromethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 039_E1 (S*)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 040_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(fluoromethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 041_E1 (S*)-N-(2-bromo-3-fluoropyridin-4-yl)-4- A (fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 042_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(fluoromethyl)-2- A methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 043_E1 (S*)-N-(4-fluoro-3-methylphenyl)-4-(fluoromethyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 044_E1 (S*)-N-(3-chloro-4,5-difluorophenyl)-4- A (fluoromethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 045 N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-N,2- B dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 046 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8,8- B trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 047 N-(3-chlorophenyl)-4-(hydroxymethyl)-2,8-dimethyl- B 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 048 N-(3-chloro-4-fluoro-phenyl)-2-methyl-4- A (methylsulfanylmethyl)-1-oxo-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine- 10-carboxamide 049_E1 (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)- B methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 049_E2 (S*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)- A methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 049_E3 (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((R*)- A methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 049_E4 (R*)-N-(3-chloro-4-fluorophenyl)-2-methyl-4-(((S*)- B methylsulfinyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 050 N-(3-chloro-4-fluorophenyl)-2-methyl-4- A ((methylsulfonyl)methyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 051 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- A 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl methyl carbonate 052 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- A 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl) methyl acetate 053 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- A 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl) methyl isopropyl carbonate 054 tert-butyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)- A 2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl) methyl) carbonate 055 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- A 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl pivalate 056 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- A 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl) methyl ethyl carbonate 057 (10-((3-chloro-4-fluorophenyl)carbamoyl)-2-methyl- A 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl carbamate 058 N-(3-chloro-4-fluoro-phenyl)-4-[(dimethylamino) A methyl]-2-methyl-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 059 [10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2-methyl- A 1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepin-4-yl]methyl N,N- dimethylcarbamate 060_E1 (S*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4- A (hydroxymethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 060_E2 (R*)-N-(3-chloro-4-fluorophenyl)-2-ethyl-4- A (hydroxymethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 061 N-(3-chloro-4-fluoro-phenyl)-2,5-dimethyl-1-oxo- A 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-10-carboxamide 062 N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo- A 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 063 N-(3-chlorophenyl)-2,4-dimethyl-1-oxo-1,4,5,8,9,11- A hexahydropyrido[4′,3′:3,4]pyrazole[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 064 N-(3-chloro-4-fluoro-phenyl)-2,4,4-trimethyl-1-oxo- A 5,8,9,11-tetrahydro pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 065 N-(3-chloro-4-fluoro-phenyl)-4-(methoxymethyl)-2- A methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 066 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo- A 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c] [1,2,5]oxadiazepine-10-carboxamide 067 2-allyl-N-(3-chloro-4-fluoro-phenyl)-1-oxo-5,8,9,11- A tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c][1,2,5] oxadiazepine-10-carboxamide 068 N-(3-chloro-4-fluoro-phenyl)-1-oxo-2-propyl- A 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-c] [1,2,5]oxadiazepine-10-carboxamide 069_E1 (4S*, 9S*)-N-(3-chloro-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 069_E2 (4R*, 9S*)-N-(3-chloro-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 069_E3 (4R*, 9R*)-N-(3-chloro-4-fluorophenyl)-4- B (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 069_E4 (4S*, 9R*)-N-(3-chloro-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 070 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)- A 2,9-dimethyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido [2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 071 methyl 10-[(3-chloro-4-fluoro-phenyl)carbamoyl]-2- D methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-4-carboxylate 072 N10-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo- A 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-4,10-dicarboxamide 073 N10-(3-chloro-4-fluoro-phenyl)-N4,2-dimethyl-1- A oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide 074 N10-(3-chloro-4-fluoro-phenyl)-N4,N4,2-trimethyl- A 1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-d][1,2,5]oxadiazepine-4,10-dicarboxamide 075 (9R)-N-(3-chloro-4-fluoro-phenyl)-2,9-dimethyl-1- A oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo [2,4-c][1,2,5]oxadiazepine-10-carboxamide 076 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,9- A dimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 077 (R)-N-(3-bromo-4-fluorophenyl)-2,9-dimethyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 078 (R)-N-(2-bromo-3-fluoropyridin-4-yl)-2,9-dimethyl- A 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 079 (R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1-oxo- A 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5]oxadiazepine-10(2H)-carboxamide 080 (R)-N-(4-fluoro-3-methylphenyl)-2,9-dimethyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 081 (R)-N-(3-chloro-4,5-difluorophenyl)-2,9-dimethyl-1- A oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 082_E1 (4S*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 082_E2 (4R*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 083_E1 (4S*, 9R)-N-(4-fluoro-3-methylphenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 083_E2 (4R*, 9R)-N-(4-fluoro-3-methylphenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 084_E1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 084_E2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 085_E1 (4S*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 085_E2 (4R*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 086_E1 (4S*, 9R)-N-(4-fluoro-3-methylphenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 086_E2 (4R*, 9R)-N-(4-fluoro-3-methylphenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 087_E1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 087_E2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 088_E1 (4S*, 9R)-N-(3-chloro-4-fluorophenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 088_E2 (4R*, 9R)-N-(3-chloro-4-fluorophenyl)-4- A (fluoromethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 089_E1 (4S*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 089_E2 (4S*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4- (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- A hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 090_E1 (4S*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 090_E2 (4R*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 091_E1 (4S*, 9R)-N-(3-chloro-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 091_E2 (4R*, 9R)-N-(3-chloro-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 092_E1 (4S*, 9R)-N-(3-bromo-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 092_E2 (4R*, 9R)-N-(3-bromo-2,4-difluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 093_D1 (4S*, 9R)-N-(3-chloro-4-fluorophenyl)-4- A ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 093_D2 (4R*, 9R)-N-(3-chloro-4-fluorophenyl)-4- A ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 094_D1 (4S*, 9R)-N-(3-bromo-4-fluorophenyl)-4- A ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 094_D2 (4R*, 9R)-N-(3-bromo-4-fluorophenyl)-4- A ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 095_D1 (4S*, 9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4- B ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 095_D2 (4R*, 9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4- B ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 096_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4- B ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 096_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4- A ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 097_D1 (4S*, 9R)-4-((dimethylamino)methyl)-N-(4-fluoro- A 3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 097_D2 (4R*, 9R)-4-((dimethylamino)methyl)-N-(4-fluoro- A 3-methylphenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 098_D1 (4S*, 9R)-4-((dimethylamino)methyl)-N-(4-fluoro- A 3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 098_D2 (4R*, 9R)-4-((dimethylamino)methyl)-N-(4-fluoro- A 3-(trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 099_D1 (4S*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4- B ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 099_D2 (4R*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4- B ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 100_D1 (4S*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4- B ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 100_D2 (4R*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4- A ((dimethylamino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 101 N-(3-chloro-4-fluoro-phenyl)-4-(ethoxymethyl)-2- A methyl-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 102 4-(allyloxymethyl)-N-(3-chloro-4-fluoro-phenyl)- A 2-methyl-1-oxo-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 103 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4- A (propoxymethyl)-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 104 N-(3-chloro-4-fluoro-phenyl)-4- A (cyclopropylmethoxymethyl)-2-methyl-1-oxo- 5,8,9,11-tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d] [1,2,5]oxadiazepine-10-carboxamide 105 N-(3-chloro-4-fluoro-phenyl)-4-(2,2- A difluoroethoxymethyl)-2-methyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 106 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4- A (2,2,2-trifluoroethoxymethyl)-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine- 10-carboxamide 107 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)-1- A oxo-2-(trideuteriomethyl)-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 108_D1 (4S*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- B difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 108_D2 (4R*, 9R)-N-(5-bromo-2,4-difluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 109_D1 (4S*, 9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- B (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 109_D2 (4S*, 9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- B (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 109_D3 (4R*, 9R*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- C (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 109_D4 (4R*, 9S*)-N-(3-chloro-4-fluorophenyl)-9-ethyl-4- B (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 110_D1 (4S*, 9R)-N10-(3-chloro-2,4-difluorophenyl)- C N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 110_D2 (4R*, 9R)-N10-(3-chloro-2,4-difluorophenyl)- A N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 111_D1 (4S*, 9R)-N10-(5-chloro-2,4-difluorophenyl)- D N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 111_D2 (4R*, 9R)-N10-(5-chloro-2,4-difluorophenyl)- A N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 112_D1 (4S*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9- D trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10 (2H)-dicarboxamide 112_D2 (4R*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4,2,9- A trimethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10 (2H)-dicarboxamide 113 4-(aminomethyl)-N-(3-chloro-4-fluoro-phenyl)-2- A methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 114_E1 (S*)-4-(aminomethyl)-N-(3-cyano-4-fluoro-phenyl)- A 2-methyl-1-oxo-5,8,9,11-tetrahydro-4H-pyrido[2,3] pyrazolo[2,4-d][1,2,5]oxadiazepine-10-carboxamide 115_D1 (4S*, 9R)-4-(aminomethyl)-N-(3-cyano-4- A fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 115_D2 (4R*, 9R)-4-(aminomethyl)-N-(3-cyano-4- N/A fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 116_D1 (4S*, 9R)-4-(aminomethyl)-N-(4-fluoro-3- A (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 116_D2 (4R*, 9R)-4-(aminomethyl)-N-(4-fluoro-3- A (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 117_D1 (4S*, 9R)-4-(aminomethyl)-N-(3-bromo-4- A fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1- d][1,2,5] oxadiazepine-10(2H)-carboxamide 117_D2 (4R*, 9R)-4-(aminomethyl)-N-(3-bromo-4- A fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 118 N10-(3-chloro-2,4-difluorophenyl)-N4,2-dimethyl- A 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 119 N10-(5-chloro-2,4-difluorophenyl)-N4,2-dimethyl- B 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 120 N10-(3-cyano-4-fluorophenyl)-N4,2-dimethyl-1- B oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 121_D1 (4S*, 9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 121_D2 (4R*, 9R)-N-(3-chloro-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 122_D1 (4S*, 9R)-N-(3-bromo-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 122_D2 (4R*, 9R)-N-(3-bromo-4-fluorophenyl)-4((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 123_D1 (4S*, 9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4- B ((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 123_D2 (4R*, 9R)-N-(2-bromo-3-fluoropyridin-4-yl)-4- A ((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 124_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 124_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 125_D1 (4S*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4- A fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 125_D2 (4R*, 9R)-4((2,2-difluoroethoxy)methyl)-N-(4- A fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 126_D1 (4S*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4- B fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 126_D2 (4R*, 9R)-4-((2,2-difluoroethoxy)methyl)-N-(4- A fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 127_D1 (4S*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4- B ((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 127_D2 (4R*, 9R)-N-(5-chloro-2,4-difluorophenyl)-4- A ((2,2-difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 128 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4- A (trifluoromethoxymethyl)-5,8,9,11-tetrahydro-4H- pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine-10- carboxamide 129 N-(3-chloro-4-fluorophenyl)-4- A (ethylsulfonamidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 130 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- A (((2,2,2-trifluoroethyl)sulfonamido)methyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 131 N-(3-chloro-4-fluorophenyl)-4-(3,3- A difluoroazetidine-1-carbonyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 132 N-(3-chloro-4-fluorophenyl)-4-(3,3- A difluoropyrrolidine-1-carbonyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 133 N10-(3-chloro-4-fluorophenyl)-N4,2-dimethyl-1- A oxo-N4-(2,2,2-trifluoroethyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 134 N10-(3-chloro-4-fluorophenyl)-N4-(2,2- A difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 135 N10-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-N4- A (2,2,2-trifluoroethyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10 (2H)-dicarboxamide 136 N10-(3-chloro-4-fluorophenyl)-N4-(2,2- A difluoroethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 137_E1 (S*)-N-(3-chloro-2,4,5-trifluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 138_E1 (S*)-N-(3-chloro-2,6-difluorophenyl)-4- B (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 139_E1 (S*)-N-(5-chloro-2-fluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 140_E1 (S*)-N-(5-bromo-2,3-difluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 141_E1 (S*)-N-(5-bromo-2-fluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 142_E1 (S*)-N-(2,4-difluoro-3-methylphenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 143_E1 (S*)-N-(2,4-difluoro-5-methylphenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 144_E1 (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N- A (2,4,5-trifluoro-3-methylphenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 145_E1 (S*)-N-(5-cyano-2-fluorophenyl)-4- D (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 146_E1 (S*)-N-(3-cyano-2-fluorophenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 147_E1 (S*)-N-(2,4-difluoro-5-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 148_E1 (S*)-N-(2-fluoro-5-(trifluoromethyl)phenyl)-4- B (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 149_E1 (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 150_E1 (S*)-N-(2-bromo-5-fluoropyridin-4-yl)-4- A (hydroxymethyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 151_E1 (S*)-4-(hydroxymethyl)-2-methyl-1-oxo-N- A (2,3,4,5-tetrafluorophenyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 152_D1 (4S*, 9R)-N10-(3-chloro-2,4-difluorophenyl)-N4- A (2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 152_D2 (4R*, 9R)-N10-(3-chloro-2,4-difluorophenyl)-N4- A (2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-4,10(2H)-dicarboxamide 153_D1 (4S*, 9R)-N10-(3-cyano-2,4-difluorophenyl)-N4- B (2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 153_D2 (4R*, 9R)-N10-(3-cyano-2,4-difluorophenyl)-N4- A (2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 154_D1 (4S*, 9R)-N10-(5-chloro-2,4-difluorophenyl)-N4- C (2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 154_D2 (4R*, 9R)-N10-(5-chloro-2,4-difluorophenyl)-N4- A (2,2-difluoroethyl)-N4,2,9-trimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 155_D1 (4S*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2- C difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 155_D2 (4R*, 9R)-N10-(3-cyano-4-fluorophenyl)-N4-(2,2- A difluoroethyl)-N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 156_D1 (4S*, 9R)-N10-(3-cyano-2,4-difluorophenyl)- D N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 156_D2 (4R*, 9R)-N10-(3-cyano-2,4-difluorophenyl)- A N4,2,9-trimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 157_D1 (4S*, 9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]- A 4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 157_D2 (4R*, 9R)-N-[2-fluoro-5-(trifluoromethyl)phenyl]- A 4-(hydroxymethyl)-2,9-dimethyl-1-oxo-5,8,9,11- tetrahydro-4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5] oxadiazepine-10-carboxamide 158 N10-(3-chloro-2,4-difluorophenyl)-N4-(2,2- A difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 159 N10-(5-chloro-2,4-difluorophenyl)-N4-(2,2- A difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 160 N10-(3-cyano-4-fluorophenyl)-N4-(2,2- A difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 161 N10-(3-cyano-2,4-difluorophenyl)-N4-(2,2- A difluoroethyl)-N4,2-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-4,10(2H)-dicarboxamide 162 4-(acetamidomethyl)-N-(3-chloro-4-fluorophenyl)- A 2-methyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-][1,2,5]doxadiazepine- 10(2H)-carboxamide 163 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- A ((2,2,2-trifluoroacetamido)methyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 164 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- B (((trifluoromethyl)sulfonamido)methyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 165 N-(3-chloro-4-fluorophenyl)-2-methyl-4- A (methylsulfonamidomethyl)-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 166 methyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)- A 2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl) methyl)carbamate 167_E1 (S*)-4-(acetamidomethyl)-N-(3-cyano-2,4- A difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 168_E1 (S*)-4-(acetamidomethyl)-N-(3-cyano-4- A fluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 169_E1 (S*)-4-(acetamidomethyl)-N-(3-chloro-2,4- A difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 170_E1 (S*)-4-(acetamidomethyl)-N-(3-bromo-2,4- A difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 171_E1 (S*)-4-(acetamidomethyl)-N-(3-bromo-4- A fluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 172_E1 (S*)-4-(acetamidomethyl)-N-(2,4-difluoro-3- A (trifluoromethyl)phenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 173_E1 (S*)-4-(acetamidomethyl)-N-(5-chloro-2,4- A difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 174_E1 (S*)-4-(acetamidomethyl)-N-(5-bromo-2,4- A difluorophenyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 175_E1 (S*)-4-(acetamidomethyl)-N-(4-fluoro-3- A (trifluoromethyl)phenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)carboxamide - 176_D1 (4S*, 9R)-4-(acetamidomethyl)-N-(3-cyano-4- B fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 176_D2 (4R*, 9R)-4-(acetamidomethyl)-N-(3-cyano-4- A fluorophenyl)-2,9-dimethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 177_D1 (4S*, 9R)-4-(acetamidomethyl)-N-(4-fluoro-3- A (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 177_D2 (4R*, 9R)-4-(acetamidomethyl)-N-(4-fluoro-3- A (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 178_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-2,9- B dimethyl-4-(methylsulfonamidomethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 178_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-2,9- A dimethyl-4-(methylsulfonamidomethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 179_D1 (4S*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)- A 2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 179_D2 (4R*, 9R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)- A 2,9-dimethyl-4-(methylsulfonamidomethyl)-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 180_D1 methyl (((4S*, 9R)-10-((3-cyano-4-fluorophenyl) A carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11- octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl)carbamate 180_D2 methyl (((4R*, 9R)-10-((3-cyano-4-fluorophenyl) A carbamoyl)-2,9-dimethyl-1-oxo-1,2,4,5,8,9,10,11- octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl)carbamate 181_D1 methyl (((4S*, 9R)-10-((4-fluoro-3- A (trifluoromethyl)phenyl)carbamoyl)-2,9-dimethyl- 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl) carbamate 181_D2 methyl (((4R*, 9R)-10-((4-fluoro-3- A (trifluoromethyl)phenyl)carbamoyl)-2,9-dimethyl- 1-oxo-1,2,4,5,8,9,10,11-octahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl)methyl) carbamate 182_D1 (4S*, 9R)-4-(((2,2-difluoroethyl)amino)methyl)-N- A (4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 182_D2 (4R*, 9R)-4(((2,2-difluoroethyl)amino)methyl)-N- A (4-fluoro-3-(trifluoromethyl)phenyl)-2,9-dimethyl- 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 183_D1 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 183_D2 (4R*, 9R)-N-(3-cyano-4-fluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 184_D1 (4S*, 9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 184_D2 (4R*, 9R)-N-(3-bromo-4-fluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 185_D1 (4S*, 9R)-4-(((2,2-difluoroethyl)amino)methyl)-N- A (4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 185_D2 (4R*, 9R)-4(((2,2-difluoroethyl)amino)methyl)-N- A (4-fluoro-3-methylphenyl)-2,9-dimethyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 186_E1 (S*)-N-(3-cyano-2,4-difluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 187_E1 (S*)-N-(3-cyano-4-fluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 188_E1 (S*)-N-(3-chloro-2,4-difluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 189_E1 (S*)-N-(3-bromo-2,4-difluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 190_E1 (S*)-N-(3-bromo-4-fluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 191_E1 (S*)-N-(2,4-difluoro-3-(trifluoromethyl)phenyl)- A 4-(((2,2-difluoroethyl)amino)methyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 192_E1 (S*)-N-(5-chloro-2,4-difluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 193_E1 (S*)-N-(5-bromo-2,4-difluorophenyl)-4-(((2,2- A difluoroethyl)amino)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 194_E1 (S*)-4-(((2,2-difluoroethyl)amino)methyl)-N- A (4-fluoro-3-(trifluoromethyl)phenyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 195 N10-(3-cyano-2,4-difluorophenyl)-N4,2-dimethyl- A 1-oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-4,10(2H)- dicarboxamide 196 N-(3-chloro-4-fluoro-phenyl)-2-methyl-1-oxo-4- N/A [(2-oxopyrrolidin-1-yl)methyl]-5,8,9,11-tetrahydro- 4H-pyrido[2,3]pyrazolo[2,4-d][1,2,5]oxadiazepine- 10-carboxamide 197 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- A (propionamidomethyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 198 N-(3-chloro-4-fluorophenyl)-4- A (cyclopropanecarboxamidomethyl)-2-methyl-1- oxo-1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 199 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- A ((3,3,3-trifluoropropanamido)methyl)-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 200 N-(3-chloro-4-fluorophenyl)-4- A (isobutyramidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 201 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo-4- A (pivalamidomethyl)-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 202 ethyl ((10-((3-chloro-4-fluorophenyl)carbamoyl)- A 2-methyl-1-oxo-1,2,4,5,8,9,10,11-octahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepin-4-yl) methyl)carbamate 203 cyclopropyl ((10-((3-chloro-4-fluorophenyl) A carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11- octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl)carbamate 204 N-(3-chloro-4-fluorophenyl)-4-((3,3-dimethylureido) A methyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 205 N-(3-chloro-4-fluorophenyl)-4-((2-cyanoacetamido) A methyl)-2-methyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 206 N-(3-chloro-4-fluorophenyl)-4-((2- A hydroxyacetamido)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 207 2,2,2-trifluoroethyl ((10-((3-chloro-4-fluorophenyl) A carbamoyl)-2-methyl-1-oxo-1,2,4,5,8,9,10,11- octahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepin-4-yl)methyl)carbamate 208 N-(3-chloro-4-fluorophenyl)-4- A (ethylsulfonamidomethyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 209 N-(3-chloro-4-fluoro-phenyl)-4-(hydroxymethyl)- C 2-methyl-1-oxo-4,5,8,9,10,11-hexahydro-[1,2,5] oxadiazepino[5,4-b]indazole-10-carboxamide 210 (4S*, 9R)-N-(3-cyano-4-fluorophenyl)-2,9- A dimethyl-1-oxo-4-((2,2,2-trifluoroethoxy)methyl)- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]oxadiazepine-10(2H)- carboxamide 211 (S*)-N-(3-cyano-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 212 (S*)-4-((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- A (trifluoromethyl)phenyl)-2-methyl-1-oxo- 1,4,5,8,9,11-hexahydropyrido[4′,3′:3,4]pyrazolo [5,1-d][1,2,5]oxadiazepine-10(2H)-carboxamide 213 (R)-N-(3-cyano-4-fluorophenyl)-2,4,4,9- A tetramethyl-1-oxo-1,4,5,8,9,11-hexahydropyrido [4′,3′:3,4]pyrazolo[5,1-d][1,2,5]oxadiazepine- 10(2H)-carboxamide 214 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,4,4,9- A tetramethyl-1-oxo-1,4,5,8,9,11- hexahydropyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5] oxadiazepine-10(2H)-carboxamide 216 N-(3-chloro-4-fluorophenyl)-2-methyl-1-oxo- B 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 217 N-(3-chloro-4-fluorophenyl)-2,3-dimethyl-1-oxo- A 1,2,3,4,5,8,9,11-octahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 218 (R)-3-allyl-N-(3-cyano-4-fluorophenyl)-2,9- A dimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 219 (R)-N-(3-cyano-4-fluorophenyl)-3-(2,2- A difluoroethyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 220 (R)-N-(3-cyano-4-fluorophenyl)-3-(2- B hydroxyethyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 221 (R)-N-(3-cyano-4-fluorophenyl)-2,9-dimethyl-1- A oxo-3-propyl-1,2,3,4,5,8,9,11-octahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 222 (R)-N-(3-cyano-4-fluorophenyl)-3-(3- B hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 223 (9R)-N-(3-cyano-4-fluorophenyl)-3-(2- B hydroxypropyl)-2,9-dimethyl-1-oxo-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 224 (R)-N-(3-cyano-4-fluorophenyl)-2,3,9-trimethyl-1- A oxo-1,2,3,4,5,8,9,11-octahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 225 (R)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-2,3,9- A trimethyl-1-oxo-1,2,3,4,5,8,9,11-octahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 226 N-(3-chloro-4-fluorophenyl)-4-hydroxy-2-methyl- D 1-oxo-4-(trifluoromethyl)-1,2,3,4,5,8,9,11- octahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 227 N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 228 N-(3-cyano-4-fluorophenyl)-4-(hydroxymethyl)-2- A methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 229 N-(3-chloro-4-fluorophenyl)-4-(1-hydroxypropyl)- B 2-methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 230 N-(3-chloro-4-fluorophenyl)-4-(1-hydroxyethyl)-2- A methyl-1-oxo-1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 231 N-(3-chloro-4-fluorophenyl)-4-(cyclopropyl B (hydroxy)methyl)-2-methyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 232 N-(3-chloro-4-fluorophenyl)-2,4-dimethyl-1-oxo- A 1,2,5,8,9,11-hexahydro-10H- pyrido[4′,3′:3,4]pyrazolo[5,1-d][1,2,5]triazepine- 10-carboxamide 233 (R)-N-(3-cyano-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 234 (R)-N-(3-bromo-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 235 (R)-N-(3-chloro-4-fluorophenyl)-4- A (hydroxymethyl)-2,9-dimethyl-1-oxo-1,2,5,8,9,11- hexahydro-10H-pyrido[4′,3′:3,4]pyrazolo[5,1-d] [1,2,5]triazepine-10-carboxamide 236 (R)-N-(3-bromo-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 237 (R)-N-(3-cyano-4-fluorophenyl)-4-((2,2- A difluoroethoxy)methyl)-2,9-dimethyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide 238 (R)-4((2,2-difluoroethoxy)methyl)-N-(4-fluoro-3- B (trifluoromethyl)phenyl)-2,9-dimethyl-1-oxo- 1,2,5,8,9,11-hexahydro-10H-pyrido[4′,3′:3,4] pyrazolo[5,1-d][1,2,5]triazepine-10-carboxamide *Pure but unknown enantiomer or diastereomer.

Example 3: Crystalline Form of Intermediate 18 Analogue

The crystalline form compound 215, which is the iodo-benzoic acid analogue of Intermediate 18, is described herein

The X-ray crystal structure is shown in FIG. 1. Table 8 also shows crystal data and structure refinement for this intermediate.

TABLE 8 Crystal data and structure refinement. Empirical formula C23 H29 I N4 O6 Formula weight 584.40 Temperature 173(2) K Wavelength 1.54178 A Crystal system, space group Monoclinic, P 21 Unit cell dimensions a = 5.2409(7) A alpha = 90 deg. b = 19.141(2) A beta = 99.804(6) deg. c = 12.9592(15) A gamma = 90 deg. Volume 1281.0(3) A{circumflex over ( )}3 Z, Calculated density 2, 1.515 Mg/m{circumflex over ( )}3 Absorption coefficient 10.196 mm{circumflex over ( )}−1 F(000) 592 Crystal size 0.25 × 0.10 × 0.08 mm Theta range for data collection 3.46 to 67.23 deg. Limiting indices −5 < = h < = 6, −22 < = k < = 22, −15 < = 1 < = 15 Reflections collected/unique 9564/4208 [R(int) = 0.0479] Completeness to theta = 67.23 97.4 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.3182 and 0.1437 Refinement method Full-matrix least-squares on F{circumflex over ( )}2 Data/restraints/parameters 4208/1/311 Goodness-of-fit on F{circumflex over ( )}2 1.087 Final R indices [I > 2sigma(I)] R1 = 0.0456, wR2 = 0.1152 R indices (all data) R1 = 0.0523, wR2 = 0.1222 Absolute structure parameter 0.078(9) Largest diff. peak and hole 0.931 and −0.569 e · A{circumflex over ( )}−3

Table 9 also shows atomic coordinates (×10⁴) and equivalent isotropic displacement parameters (A²×10³) for the intermediate.

TABLE 9 Atomic coordinates and equivalent isotropic displacement parameters. x y z U(eq) I(1) 2937(1) 5453(1) −515(1) 50(1) O(1) 8677(10) 4897(2) 4622(4) 48(1) O(2) 8496(10) 3521(2) 6400(4) 46(1) O(3) 12572(11) 2866(3) 7830(5) 57(1) O(4) −1079(9) 6970(2) 3889(4) 46(1) N(1) 6070(10) 4702(3) 7026(4) 37(1) N(2) 4327(11) 5136(3) 7358(4) 40(1) N(3) 2310(10) 6353(3) 4757(4) 38(1) N(4) 9283(13) 3932(3) 5604(5) 49(1) C(1) 9483(14) 3805(4) 7432(6) 46(2) C(2) 7211(14) 4172(3) 7782(5) 43(1) C(3) 3569(11) 5571(3) 6568(4) 35(1) C(4) 1694(12) 6154(3) 6567(5) 39(1) C(5) 2121(14) 6704(3) 5762(5) 40(1) C(6) 4451(13) 5851(3) 4740(5) 40(1) C(7) 4851(9) 5429(4) 5724(4) 34(1) C(8) 6436(12) 4862(3) 6034(5) 35(1) C(9) 8225(13) 4557(3) 5371(5) 37(1) C(10) 10442(15) 3215(4) 8132(6) 50(2) C(11) 11166(16) 3614(4) 5079(6) 52(2) C(12) 712(12) 6552(3) 3879(5) 36(1) C(13) 1240(12) 6265(3) 2862(5) 35(1) C(14) 3170(15) 6560(4) 2406(6) 49(2) C(15) 3618(15) 6325(4) 1444(6) 50(2) C(16) 2130(14) 5808(4) 930(5) 44(2) C(17) 236(14) 5506(6) 1390(5) 51(2) C(18) −282(15) 5735(4) 2335(6) 49(2) C(19) 4496(15) 7147(4) 6121(7) 54(2) O(1′) −1840(30) 3792(6) 473(10) 152(4) O(2′) −3660(40) 3365(8) 1631(11) 175(6) C(1′) −640(100) 2470(14) 770(30) 340(30) C(2′) −2150(90) 3320(20) 969(15) 340(30) C(3′) −4410(30) 4042(6) 1973(13) 110(4) C(4′) −5960(40) 3988(9) 2697(16) 138(6)

As can be seen, the stereo configuration of the Intermediate 18 analogue is 4S, 9R. Accordingly, the stereo configuration of compounds derived from Intermediate 18 is known.

The disclosures of each and every patent, patent application, and publication cited herein are hereby incorporated herein by reference in their entirety.

While the invention has been disclosed with reference to specific embodiments, it is apparent that other embodiments and variations of this invention may be devised by others skilled in the art without departing from the true spirit and scope of the invention. The appended claims are intended to be construed to include all such embodiments and equivalent variations. 

1-25. (canceled)
 26. A compound of Formula II:

or a pharmaceutically acceptable salt thereof; wherein R¹ is C₁-C₆-alkyl; R² is, at each occurrence, independently selected from C₁-C₆-alkyl and C₁-C₆-alkyl-OR⁶, wherein alkyl is optionally substituted with 1,2, or 3 groups, each independently selected from —OH and halo; or R² is at each occurrence, independently selected from —CH₂OCH₂-cyclopropyl, —CH₂OCH₂CH═CH₂, —CH₂SCH₃, —CH₂S(O)CH₃, —CH₂—S(O)₂CH₃, —CH₂OC(O)OCH₃, —CH₂OC(O)OCH(CH₃)₂, —CH₂OC(O)OC(CH₃)₃, —CH₂OC(O)OCH₂CH₃, —CH₂OC(O)CH₃, —CH₂OC(O)C(CH₃)₃, —C(O)OH, —C(O)OCH₃, —CH₂OC(O)NH₂, —CH₂OC(O)N(CH₃)₂, —C(O)NH₂, —C(O)NHCH₃, —C(O)N(CH₃)₂, and —CH₂N(CH₃)₂; R³ is, at each occurrence, independently selected from C₁-C₆-alkyl; R⁴ is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with 1-3 groups independently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl; R⁵ is H; R⁶ is C₁-C₆-alkyl or C₁-C₆-haloalkyl; and n is 0, 1, or
 2. 27. The compound of claim 26, wherein R¹ is CH₃.
 28. The compound of claim 26, wherein R² is, at each occurrence, independently selected from —CH₃—CH₂OH, —CH₂F, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂OCH₂CH₂CH₃, —CH₂OCH₂CHF₂, and —CH₂OCH₂CF₃.
 29. The compound of claim 26, wherein R² is C₁-C₆-alkyl optionally substituted with 1, 2, or 3 halo groups.
 30. The compound of claim 26, wherein R² is (CH₂)₁₋₂—O—C₁-C₃-alkyl, wherein C₁-C₃-alkyl is optionally substituted with 1,2, or 3 halo groups.
 31. The compound of claim 26, wherein R³ is C₁-C₃-alkyl.
 32. The compound of claim 26, wherein R³ is —CH₃.
 33. The compound of claim 26, wherein R⁴ is phenyl substituted with 1-3 groups independently selected from halo, —CN, C₁-C₆-alkyl, and C₁-C₆-haloalkyl.
 34. The compound of claim 26, wherein R⁵ is H.
 35. The compound of claim 26, wherein R¹ is C₁-C₆-alkyl; R⁴ is phenyl substituted with at least one halogen; and R⁵ is H.
 36. The compound of claim 26, wherein R¹ is C₁-C₆-alkyl; R² is selected from the group consisting of CH₂OH, —CH₂OCH₂CHF₂ or —CH₂OCH₂CF₃; R⁴ is phenyl substituted with at least one halogen; and R⁵ is H.
 37. The compound of claim 26, wherein the compound of Formula II is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 38. A pharmaceutical composition comprising a compound of claim 26, and a pharmaceutically acceptable carrier.
 39. A method of treating an HBV infection in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of claim
 26. 40. A method of inhibiting or reducing the formation or presence of HBV DNA-containing particles or HBV RNA-containing particles in an individual, comprising administering to the individual a therapeutically effective amount of a compound of claim
 26. 41. The method of claim 40, further comprising administering to the individual at least one additional therapeutic agent selected from the group consisting of an HBV polymerase inhibitor, immunomodulatory agents, interferon, viral entry inhibitor, viral maturation inhibitor, capsid assembly modulator, reverse transcriptase inhibitor, cyclophilin/TNF inhibitor, TLR-agonist, HBV vaccine, and any combination thereof. 